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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)
Bone Cancer
Version 2.2017 November 7, 2016
NCCN.org
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NCCN Guidelines Version 2.2017 Panel Members NCCN Guidelines Index

Table of Contents
Bone Cancer Discussion
*J. Sybil Biermann, MD/Chair Nicola Fabbri, MD R. Lor Randall, MD

University of Michigan Memorial Sloan Kettering Cancer Center Huntsman Cancer Institute
Comprehensive Cancer Center at the University of Utah
Francis J. Hornicek, MD, PhD
*Warren Chow, MD/Vice-Chair Massachusetts General Hospital Damon R. Reed, MD
City of Hope Cancer Center Moffitt Cancer Center
Comprehensive Cancer Center
Joseph B. Kuechle, MD, PhD Peter Rose, MD
Douglas R. Adkins, MD Roswell Park Cancer Institute Mayo Clinic Cancer Center
Siteman Cancer Center
at Barnes-Jewish Hospital Dieter Lindskog, MD Victor M. Santana, MD
and Washington University Yale Cancer Center/ St. Jude Childrens Research Hospital/The
School of Medicine Smilow Cancer Hospital University of Tennessee Health Science Center
Mark Agulnik, MD David Lucas, MD Robert L. Satcher, MD, PhD

Robert H. Lurie Comprehensive Cancer University of Michigan The University of Texas
Center of Northwestern University Comprehensive Cancer Center MD Anderson Cancer Center
Robert S. Benjamin, MD Joel Mayerson, MD Herbert Schwartz, MD

The University of Texas The Ohio State University Comprehensive Vanderbilt-Ingram Cancer Center
MD Anderson Cancer Center Cancer Center - James Cancer Hospital
and Solove Research Institute Herrick J. Siegel, MD
Brian Brigman, MD, PhD University of Alabama at Birmingham
Duke Cancer Institute Sean V. McGarry, MD Comprehensive Cancer Center
Fred & Pamela Buffett Cancer Center
G. Thomas Budd, MD Katherine Thornton, MD
Case Comprehensive Cancer Center/ Lynn Million, MD Dana-Farber/Brigham and Women's Cancer Center
University Hospitals Seidman Cancer Center Stanford Cancer Institute
Victor Villalobos, MD, PhD
and Cleveland Clinic Taussig Cancer Institute
Carol D. Morris, MD, MS University of Colorado Cancer Center
William T. Curry, MD The Sidney Kimmel Comprehensive
Surgery/Surgical oncology
Massachusetts General Hospital Cancer Center at Johns Hopkins
Medical oncology
Cancer Center Hematology/Hematology oncology
Sujana Movva, MD
Fox Chase Cancer Center Radiotherapy/Radiation oncology
Aarati Didwania, MD
Orthopedics
Robert H. Lurie Comprehensive Cancer Pediatric oncology
Center of Northwestern University Richard J. ODonnell, MD
Pathology
UCSF Helen Diller Family
NCCN Comprehensive Cancer Center
Mary Anne Bergman *Discussion Writing Committee Member
Jillian Scavone, PhD NCCN Guidelines Panel Disclosures
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NCCN Guidelines Version 2.2017 Table of Contents NCCN Guidelines Index

Table of Contents
NCCN Bone Cancer Panel Members Osteosarcoma:

Summary of the Guidelines Updates Workup and Primary Treatment (OSTEO-1)
Neoadjuvant and Adjuvant Treatment (OSTEO-2)
Multidisciplinary Team (TEAM-1) Metastatic Disease (OSTEO-3)
Bone Cancer Workup (BONE-1) Surveillance and Relapse (OSTEO-4)
Chondrosarcoma: Principles of Bone Cancer Management (BONE-A)
Presentation and Primary Treatment (CHON-1) Bone Cancer Systemic Therapy Agents (BONE-B)
Principles of Radiation Therapy (BONE-C)
Chordoma: Staging (ST-1)
Workup and Histologic Subtype (CHOR-1)
Presentation and Primary Treatment (CHOR-2)
Surveillance and Recurrence (CHOR-3)
Ewing Sarcoma: Clinical Trials: NCCN believes that the best management of any
Workup and Primary Treatment (EW-1) patient with cancer is in a clinical trial.
Participation in clinical trials is especially encouraged.
Adjuvant Treatment, Surveillance, and Relapse (EW-2)
To find clinical trials online at NCCN Member Institutions, click here:
nccn.org/clinical_trials/physician.html.
Giant Cell Tumor of the Bone:
NCCN Categories of Evidence and Consensus: All
Workup and Presentation (GCTB-1) recommendations are category 2A unless otherwise specified.
Primary Treatment (GCTB-2) See NCCN Categories of Evidence and Consensus.
Surveillance (GCTB-3)
The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patients care or treatment. The National Comprehensive Cancer Network (NCCN) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. 2016.
NCCN Guidelines Version 2.2017 Updates NCCN Guidelines Index

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Updates in Version 2.2017 of the NCCN Guidelines for Bone Cancer from Version 1.2017 include:
MS-1: The discussion section has been updated to reflect the changes in the algorithm.
Chondrosarcoma:
CHON-1
Low Grade/Under Surveillance:
2nd bullet modified: "Radiographs of primary site and/or cross-sectional imaging MRI or CT (both with contrast) as clinically indicated every 612 mo for
2 y then yearly as appropriate." (Also for the High-grade).
High Grade/Under Surveillance:
3rd bullet modified: "Chest imaging every 36 mo may include CT at least every 6 mo for 5 y, then yearly for a minimum of 10 y."
Footnote "g", "Based on physician's concern for risk of recurrence" is new to the page and corresponds to chest imaging.
For Low grade/High grade, Local recurrence, "Consider RT" is a category 2B recommendation.
For Systemic recurrence, "cyclophosphamide and sirolimus" has been removed. (Also for BONE-B).
Chordoma:
CHOR-1
3rd bullet modified to include "CT MRI [both with contrast]." (Also for CHOR-3).
"CT" has been added to PET throughtout the guidelines: "PET/CT."
CHOR-2
Skull base/Clival, 3rd column modified to include "Follow-up MRI of primary site with contrast to assess adequacy of resection."
CHOR-3
3rd bullet modified: "Chest imaging every 6 mo may include CT annually for 5 y, then annually therafter."
4th bullet modified: "Cross-sectional abdominal CT of abdomen and pelvis with contrast imaging annually."
Ewing Sarcoma:
EW-1
"Ewing's Sarcoma Family of Tumors" has been modified to "Ewing Sarcoma" throughout the guidelines.
Workup, 2nd bullet modified: "MRI MRI CT (both with contrast) of primary site." (Also for OSTEO-1).
For patients with localized disease, bullets modified as follows:
"CT Chest imaging"
"Imaging MRI CT (both with contrast) of primary site."
"Radiographs of primary site" is new to the page. (Also for patients with metastatic disease)
EW-2
4th column
1st bullet modified: "Physical exam, imaging."
2nd bullet modified: "MRI CT (both with contrast) of primary site."
Giant Cell Tumor of the Bone:

GCTB-1
Workup: 2nd bullet modified: "Imaging (eg, x-ray, CT MRI [both with contrast]) of primary site as clinically indicated." (Also for GCTB-3).
GCTB-2
Localized disease, 4th column,"Imaging to assess response, plain radiographs and CT MRI (both with contrast)" is new to the page.
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Osteosarcoma
OSTEO-1
Workup, 5th bullet modified: MRI or CT (both with contrast) of skeletal metastatic sites.
OSTEO-2
Restage: "Radiographs of primary site" is new to the page.
"Or continue with preoperative regimen" was added for clarification under Adjuvant Treatment, for "consider changing chemotherapy."
OSTEO-4
4th column is new to the page:
Imaging to assess response
Radiographs of primary site
CT and/or MRI (both with contrast) of local sites
Chest CT.
Bone Cancer Systemic Therapy Agents:

BONE-B
Under Chordoma:
"Sorafenib" is new to the page with the following references:
-Amela E, Bompas E, Le Cesne A, et al. A phase II trial of sorafenib (SO) in advanced chordoma patiets (pt). J Clin Oncol 2015; 33(15):Supplement 10520.
-Bompas E, Le Cesne A, Tresch-Bruneel E, et al. Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French
Sarcoma Group (GSF/GETY). Ann Oncol 2015;10:2168-2173.
Peginterferon was removed for Giant Cell Tumor of Bone.
Principles of Radiation Therapy:

BONE-C (2 of 5)
Ewing Sarcoma:
Treatment volumes and doses, 1st sub-sub-bullet modified:
45 Gy to initial gross tumor volume (GTV1) + 11.5 cm for clinical target volume 1 (CTV1) + 0.51 cm for planning target volume 1 (PTV1)GTV1 defined
as: pre-treatment extent of bone and soft tissue disease. If the tumor has responded to chemotherapy and normal tissues have returned to their
natural position, GTV1 should exclude pre-chemotherapy soft tissue volume that extended into a cavity
(eg, tumors indenting lung, intestine, or bladder resume normal position following chemotherapy).
Hemithorax Irradiation, 1st sub-bullet modified:
"Should be considered for chest wall primaries with extensive ipsilateral pleural involvement or malignant pleural effusion."
Treatment of Metastatic Disease:
"Whole-lung irradiation following completion of chemotherapy-metastasectomy is a (category 3) recommendation. A corresponding reference has been
added: "Tanguturi SK, George S, Marcus KJ, et al. Whole lung irradiation in adults with metastatic Ewing Sarcoma: Practice patterns and implications for
treatment. Sarcoma 2015, Article ID 591698 5 pages; http://dx.doi.org/10.1155/2015/591698."

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Team Approach Discussion
MULTIDISCIPLINARY TEAM
Primary bone tumors and selected metastatic tumors should be evaluated and treated by a multidisciplinary team with
expertise in the management of these tumors. The team should meet on a regular basis and should include:
Core Group
Musculoskeletal oncologist
Bone pathologist
Medical/pediatric oncologist
Radiation oncologist
Musculoskeletal radiologist
Specialists Critical in Certain Cases

Thoracic surgeon
Plastic surgeon
Interventional radiologist
Physiatrist
Vascular/general surgeon
Neurosurgeon
Additional surgical subspecialties as clinically indicated

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WORKUP
Refer to orthopedic
See Bone Cancer
oncologist
Table of Contents
<40 Biopsy should be
for specific bone
performed at
sarcomas
treating institutionb
Refer to
Symptomatic Abnormal orthopedic
bone lesiona radiograph No other lesions oncologist
(Possible bone Biopsy should
History and physical primary) be performed
Bone scan at treating
Workup for Chest radiograph institution
potential bone SPEP/labs
40
metastasis as Chest/abdominal/
clinically indicated pelvic CT
PSA Refer to
Mammogram Other lesions appropriate NCCN
(Non-bone primary Guidelines for
suspected) treatment of
cancer by site
aSee Multidisciplinary Team (TEAM-1).

bSee Principles of Bone Cancer Management (BONE-A).

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Chondrosarcoma Discussion
Consider RTf
PRESENTATIONa,b,c PRIMARY SURVEILLANCE RECURRENCE
(category 2B)
TREATMENT Physical exam
Intralesional Positive or
Radiographs of primary Wide margins Consider re-resection
excisiond surgical
site and/or cross-sectional excision,e to achieve negative
adjuvant
imaging MRI or CT (both if surgical margins
or
Low grade with contrast) as clinically resectable
Wide excision,e Local
and indicated every 612 mo or Negative
if resectable recurrence Observe
Intracompartmental for 2 y then yearly as f
RT, if margins
or
appropriate unresectable
Consider RT,f
Chest imaging as clinically (category 2B) Consider RTf
if unresectable
indicated every 612 months (category 2B)
(category 2B) Positive
then yearly as appropriate or
Wide margins
Physical exam Consider re-resection
excision,e
Radiographs of primary to achieve negative
if
Wide site and/or cross-sectional Local surgical margins
High grade resectable
excision,e imaging MRI or CT (both or Negative
(grade ll, grade lll) recurrence Observe
if resectable with contrast) as clinically f
RT, if margins
or
Clear cell or indicated unresectable
or Consider RT,f Chest imagingg (category 2B)
Extracompartmental if unresectable every 36 mo may include
(category 2B) CT at least every 6 mo for 5
y, then yearly for a minimum Clinical trial (preferred)
of 10 y Systemic or
Reassess function at every recurrence Surgical excisionb
follow-up visit
Treat as osteosarcoma (category 2B)
Dedifferentiated
See NCCN Guidelines for Osteosarcoma (OSTEO-1)
Treat as Ewing sarcoma (category 2B)
Mesenchymal
See NCCN Guidelines for Ewing Sarcoma (EW-1)
aSee Multidisciplinary Team (TEAM-1). dThis management should be restricted to extremity tumors (not pelvic tumors).
bSee Principles of Bone Cancer Management (BONE-A). eWide excision should provide histologically negative surgical margins. This may be
cThere is considerable controversy regarding the grading of chondrosarcoma. In achieved by either limb-sparing resection or limb amputation.
addition to histology, radiologic features, size, and location of tumors should also fSee Principles of Radiation Therapy (BONE-C).
be considered in deciding local treatment. gBased on physician's concern for risk of recurrence.

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Chordoma Discussion
WORKUPa,b HISTOLOGIC SUBTYPE
Conventional
See Presentation and Primary
or
Treatment (CHOR-2)
All patients should be evaluated and Chondroid
treated by a multidisciplinary team with
expertise in the management of chordomaa
History and physical
Adequate imaging (eg, x-ray, CT MRI
[both with contrast]) of primary site and
screening MRI of spinal axis
CT of chest, abdomen, and pelvis
Consider PET/CT
Consider bone scan if PET/CT is negative
Biopsy to confirm histologic subtypeb,c
See NCCN Guidelines
Dedifferentiated
for Soft Tissue Sarcoma

cBiopsy should be done after imaging studies are completed; biopsy type may vary depending on anatomic location. Optimally, biopsy should be performed at a center
of excellence where definitive management is given. Cord compression may limit surgical procedures.

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Chordoma Discussion
PRESENTATION PRIMARY TREATMENT ADJUVANT TREATMENT
Wide resectionb Consider RTd,e

RT,d,e for positive surgical margins or for
if resectable large extracompartmental tumors
Sacrococcygeal
and OR
Mobile spine
Consider RTe
if unresectable
See
Surveillance
Follow-up MRI (CHOR-3)
Consider RTd,e
Intralesional excisionf of primary site
for positive surgical margins or for
RT,d,e with contrast to
large extracompartmental tumors
if resectable assess adequacy
Consider re-resectionb if necessary
of resection
Skull base/Clival OR
Consider RTe
if unresectable

dRadiation therapy may be given preoperatively, intraoperatively, and/or postoperatively.
eSee Principles of Radiation Therapy (BONE-C).
fMaximal safe resection. Maximal tumor removal is recommended when appropriate.


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Chordoma Discussion
SURVEILLANCE RECURRENCE TREATMENT
Surgical excisionb
and/or
Physical exam Local
RTe
Imaging (eg, x-ray, CT recurrence
and/or
MRI [both with contrast]) Systemic therapyg
of surgical site as clinically
indicated
Chest imaging every 6 mo
may include CT annually Systemic therapyg
for 5 y, then annually and/or
thereafter Surgical excisionb
CT of abdomen and pelvis Metastatic
and/or
with contrast annually recurrence
RTe
and/or
Best supportive care

eSee Principles of Radiation Therapy (BONE-C).
gSee Bone Cancer Systemic Therapy Agents (BONE-B).

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Ewing Sarcoma Discussion
PRESENTATIONa,b,c WORKUP PRIMARY RESTAGE

TREATMENT
For patients with
localized disease
Restage with:
History and physical CT Chest
MRI CT (both with MRI CT (both with
contrast) of primary site contrast) of primary
CT Chest See Stable/
site
PET/CT and/or bone improved
Radiographs of
scan Multiagent Response disease following
primary site
Bone marrow biopsy chemotherapyf response to
Consider PET/CT or
and/or screening MRI of (category 1) primary treatment
Ewing sarcoma bone scang
spine and pelvisd for at least (EW-2)
Cytogenetics and/or 12 weeks prior For patients with
molecular studiese to local metastatic disease See Progressive
(may require re-biopsy) therapyh Restage with: Progressive disease following
LDH CT Chest disease primary treatment
Fertility consultation MRI CT (both with (EW-2)
should be considered contrast) of primary
site
Radiographs of
primary site
Consider PET/CT or
bone scang
Repeat other
abnormal studies
cEwing sarcoma can be treated using this algorithm, including primitive neuroectodermal tumor of bone, Askins tumor, and extraosseous Ewing sarcoma.
dKumar J, Seith A, Kumar A, et al. Whole-body MR imaging with the use of parallel imaging for detection of skeletal metastases in pediatric patients with
small cell neoplasms: comparison with skeletal scintigraphy and FDG PET/CT. Pediatr Radiol 2008;38:953-962. Epub 2008 Jul 18.
e90% of Ewing sarcoma will have one of four specific cytogenetic translocations.
fSee Bone Cancer Systemic Therapy Agents (BONE-B).
gUse the same imaging technique that was performed in the initial workup.
hLonger primary treatment duration can be considered in patients with metastatic disease based on response.

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Ewing Sarcoma Discussion
LOCAL CONTROL ADJUVANT TREATMENT/ PROGRESSIVE

SURVEILLANCE
THERAPY ADDITIONAL THERAPY DISEASE/RELAPSE
Physical exam
MRI CT (both with
Continue chemotherapyf,j contrast) of primary
(category 1) followed by RTl site
Positive or Chest CT every 23
margins RTl and chemotherapyf,j mo
(category 1, for Radiographs of
Wide excisionb chemotherapy) Early
primary site
CBC and other relapse
Negative Chemotherapyf,j
or
marginsi (category 1) laboratory studies
as indicated Chemotherapyf,k
Stable/improved Definitive RTl and chemotherapyf,j Increase intervals
disease following for physical exam, RTl
response to or imaging of primary
primary treatment Postoperative Late
site and chest after
chemotherapy,f relapsek
24 mo and annually
Amputationb in selected cases consider RTl
after 5y (indefinitely)
depending on
(category 2B)
margin status
Consider PET/CT
or bone scang
Progressive disease Consider RTl and/or Chemotherapyf

following primary surgery to primary or
treatment site for local control Best supportive
or palliation care
fSee Bone Cancer Systemic Therapy Agents (BONE-B).
gUse the same imaging technique that was performed in the initial workup.
iRT may be considered for close margins.
jThere is category 1 evidence for between 28 and 49 weeks of chemotherapy depending on the chemotherapy and dosing schedule used.
kFor late relapse, consider re-treatment with previously effective regimen.
lSee Principles of Radiation Therapy (BONE-C).

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Giant Cell Tumor of the Bone Discussion
WORKUP PRESENTATION
Localized disease See GCTB-2
History and physical examination

Imaging (eg, x-ray, CT MRI [both with contrast]) of
primary site as clinically indicated
Chest imaging
Bone scan (optional)
Biopsy to confirm diagnosisa,b
If there is malignant transformation, treat as described for
osteosarcoma. (See OSTEO-1)
Metastatic disease
See GCTB-2
at presentation
aBrown tumor of hyperparathyroidism should be considered as a differential diagnosis.


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PRIMARY TREATMENT
Resectable Excisionc See

Surveillance
Localized Stable/improved (GCTB-3)
disease disease
See
Serial Imaging to Changes to
Resectable Excisionc Surveillance
embolization assess resectable
with (GCTB-3)
and/or response, Stable/improved
unacceptable
Denosumabd,e plain disease with
morbidity
and/or radiographs incomplete
and/or
IFNe and CT MRI healing
Unresectable See
axial lesions and/or (both with Remains
Surveillance
RTf,h contrast) unresectable
(GCTB-3)
Progressive
disease
For primary tumor, treat as above

Resectable
Consider excisionc of metastatic sites
Metastatic
See
disease at
Surveillance
presentationg Consider the following options: (GCTB-3)
Denosumab
Unresectable IFNe
RTh
Observation
cIntralesional excision with an effective adjuvant is adequate. f RT has been associated with increased risk of malignant transformation.
dDenosumab should be continued until disease progression in responding gTreatment of primary tumor is as described for localized disease.
disease. hSee Principles of Radiation Therapy (BONE-C).
eSee Bone Cancer Systemic Therapy Agents (BONE-B).


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SURVEILLANCE RECURRENCE
Consider chest Consider denosumab prior

Resectable
imaging to surgery (See GCTB-2)
Local
recurrence
Physical exam Resectable

Imaging (x-ray, CT MRI with
[both with contrast]) of unacceptable
surgical site as morbidity See GCTB-2
clinically indicated or
Chest imaging every unresectable
6 mo for 2 years then axial lesions
annually thereafter
Metastatic
See GCTB-2
recurrence


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Osteosarcoma Discussion
WORKUPa,b PRIMARY TREATMENT ADJUVANT TREATMENT
Low-grade osteosarcoma:c Wide High Chemotherapyd

History and Intramedullary + surface excisionb grade (category 2B)
physical
MRI CT (both
with contrast) of
primary site See
Periosteal Consider Wide Surveillance
Chest imaging Low
osteosarcoma chemotherapyd excisionb (OSTEO-4)
including grade
chest CT
PET/CT and/or
bone scan
MRI or CT (both
with contrast) of High-grade
skeletal osteosarcoma:
(OSTEO-2)
metastatic sitese Intramedullary
LDH + surface
ALP
Fertility
consultation Metastatic disease
should be (OSTEO-3)
at presentation
considered
Extraskeletal See NCCN Guidelines for
osteosarcoma Soft Tissue Sarcoma
cDedifferentiated parosteal osteosarcomas are not considered to be low-grade tumors.
dSee Bone Cancer Systemic Therapy Agents (BONE-B).
eMore detailed imaging (CT or MRI) of abnormalities identified on primary imaging is required for suspected metastatic disease.

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NEOADJUVANT ADJUVANT TREATMENT

TREATMENT RESTAGE
RTh
Unresectable Chemotherapyd
Reassess
Chemotherapyd
tumor as Consider
appropriate Good additional local
Restage with responseh therapy (surgical
pretreatment resectionb RT)i
imaging
modalities: Consider
High-grade CT Chest Positive additional local
Preoperative margins
osteosarcoma:j MRI CT therapy (surgical
chemotherapyd,g
Intramedullary (both with resectionb RT)i
(category 1) Continue with
+ surface contrast) of Poor
primary site preoperative
responseh See
Radiographs regimen
or Surveillance
of primary
Wide Consider changing (OSTEO-4)
site Resectable
excisionb chemotherapyd,f
Consider (category 2B)
PET/CT or
bone scang Good
Chemotherapyd
responseh
Continue with
Negative preoperative
margins regimen
Poor or
responseh Consider
changing
chemotherapyd,f
(category 2B)
bSee Principles of Bone Cancer Management (BONE-A). reported as less than 10% of the tumor area in cases showing a good response and greater than or
dSee Bone Cancer Systemic Therapy Agents (BONE-B). equal to 10% in cases showing a poor response.
fSee discussion for further information (MS-1) iSee Principles of Radiation Therapy (BONE-C).
gSelected elderly patients may benefit from immediate surgery. jOther high-grade non-osteosarcoma variants such as undifferentiated pleomorphic sarcoma (UPS) of
hResponse is defined by pathologic mapping per institutional guidelines; the amount of viable tumor is bone could also be treated using this algorithm.


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PRESENTATION PRIMARY TREATMENT
See OSTEO-2 for

management of
Resectable (pulmonary, primary tumor
visceral, or skeletal metastases) Chemotherapyd
Metastasectomyb
Metastatic disease Surveillance (See

at presentation OSTEO-4)
Chemotherapyd
RTi
Unresectable Reassess primary site
as appropriate for
local control

iSee Principles of Radiation Therapy (BONE-C).


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SURVEILLANCE RELAPSE
Physical exam, imaging of

primary site and chestk Imaging Response Surveillance
Follow-up schedule: to assess
(Orthopedic and Oncologic) response:
Every 3 months for y 1 and 2 Radiographs Resection,b if possible
Every 4 months for y 3 Chemotherapyd of primary or
Every 6 months for y 4 and 5 Relapse and/or resection site Clinical trial
and yearly thereafter if possible CT and/or MRI or
CBC and other laboratory (both with Samarium-153 ethylene diamine
studies as clinically indicated contrast) of tetramethylene phosphonate
Consider PET/CT and/or bone local sites Relapse/ (153Sm-EDTMP)
scan (category 2B) Chest CT Progression and
Reassess function every visit Radium dichloride
(Ra 223)i,l,m,n
or
Palliative RTi
or
Best supportive care

iSee Principles of Radiation Therapy (BONE-C)
kUse the same imaging technique that was performed in the initial workup.
lSubbiah V; Anderson PM; Rohren E. Alpha Emitter Radium 223 in High-Risk Osteosarcoma: First Clinical Evidence of Response and Blood-Brain Barrier Penetration.
JAMA Oncol 2015;1(2):253-255.
mAnderson PM; Subbiah V; Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153-EDTMP and Radium-223. Adv Exp Med
Biol 2014;804:291-304.
nSubbiah V; Rohren E; Huh WW; Kappadath CS; Anderson PM. Phase 1 dose escalation trial of intravenous radium 223 dichloride alpha-particle therapy in
osteosarcoma. J Clin Oncol 2014;32(5s): Abstract TPS10600. Presented at the 2014 ASCO Annual Meeting, Chicago, IL, United States.


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PRINCIPLES OF BONE CANCER MANAGEMENT
Biopsy
Biopsy diagnosis is necessary prior to any surgical procedure or fixation of primary site.
Biopsy is optimally performed at a center that will do definitive management.
Placement of biopsy is critical.
Biopsy should be core needle or surgical biopsy.
Technique: Apply same principles for core needle or open biopsy. Needle biopsy is not recommended for skull base tumors.
Appropriate communication between the surgeon, musculoskeletal radiologist, and bone pathologist is critical.
Fresh tissue may be needed for molecular studies and tissue banking.
In general, failure to follow appropriate biopsy procedures may lead to adverse patient outcomes.
Surgery
Wide excision should achieve histologically negative surgical margins.
Negative surgical margins optimize local tumor control.
Local tumor control may be achieved by either limb-sparing resection or limb amputation (individualized for a given patient).
Limb-sparing resection is preferred to optimize function if reasonable functional expectations can be achieved.
Final pathologic evaluation should include assessment of surgical margins and size/dimensions of tumor.
Lab Studies
Lab studies such as CBC, LDH, and ALP may have relevance in the diagnosis, prognosis, and management of bone sarcoma
patients and should be done prior to definitive treatment and periodically during treatment and surveillance.
Treatment
Fertility issues should be addressed with patients prior to commencing chemotherapy.
Care for bone cancer patients should be delivered directly by physicians on the multidisciplinary team (category 1).
See TEAM-1.
Long-Term Follow-up and Surveillance/Survivorship

Patients should have a survivorship prescription to schedule follow-up with a multidisciplinary team.
Life-long follow-up is recommended for surveillance and treatment of late effects of surgery, radiation, and chemotherapy in
long-term survivors.
See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology (1539 years old) as clinically appropriate.

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BONE CANCER SYSTEMIC THERAPY AGENTS

Second-line therapy (relapsed/refractory or metastatic disease)
Chondrosarcoma
Cyclophosphamide and topotecan17-20
Conventional chondrosarcoma (Grades 13) has no known standard
Irinotecan temozolomide21-27
chemotherapy options
Ifosfamide (high dose) etoposide28, 29
Mesenchymal chondrosarcoma: Follow Ewing sarcoma regimens
Ifosfamide, carboplatin, and etoposide30
(category 2B)
Docetaxel and gemcitabine31
Dedifferentiated chondrosarcoma: Follow osteosarcoma regimens
(category 2B)
Giant Cell Tumor of Bone
Denosumab32-34
Chordoma
Interferon alfa34-36
Imatinib1,2,3
Imatinib with cisplatin4 or sirolimus5
Osteosarcoma
Erlotinib6
First-line therapy (primary/neoadjuvant/adjuvant therapy or metastatic
Sunitinib7
disease)
Lapatinib for EGFR-positive chordomas8 (category 2B)
Cisplatin and doxorubicin37-39
Sorafenib9,10
MAP (High-dose methotrexate, cisplatin, and doxorubicin)40-41
Doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate42
Ewing Sarcoma
Ifosfamide, cisplatin, and epirubicin43
First-line therapy (primary/neoadjuvant/adjuvant therapy)
VAC/IE
Second-line therapy (relapsed/refractory or metastatic disease)
(vincristine, doxorubicin, and cyclophosphamide alternating with
Docetaxel and gemcitabine31
ifosfamide and etoposide)11,12,
Cyclophosphamide and etoposide44
VAI (vincristine, doxorubicin, and ifosfamide)13,14
Cyclophosphamide and topotecan20
VIDE (vincristine, ifosfamide, doxorubicin, and etoposide)15
Gemcitabine45
Ifosfamide (high dose) etoposide28, 46
Primary therapy for metastatic disease at initial presentation
Ifosfamide, carboplatin, and etoposide30
VAdriaC (vincristine, doxorubicin, and cyclophosphamide)16
High-dose methotrexate, etoposide, and ifosfamide47
VAC/IE11
153Sm-EDTMP for relapsed or refractory disease beyond second-line
VAI13,14
therapy48
VIDE15
Ra 22349-51
Sorafenib52
Sorafenib + everolimus53
High-Grade Undifferentiated Pleomorphic Sarcoma (UPS)

Follow osteosarcoma regimens (category 2B)
Chemotherapy should include growth factor support (See NCCN Guidelines for Myeloid Growth Factors).
Dactinomycin can be substituted for doxorubicin for concerns regarding cardiotoxicity.
In patients younger than 18 y, evidence supports 2-week compressed treatment.
Vincristine could be added to any of the regimens.
References on next page
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2Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer 2004;101:2086-2097.
3Stacchiotti S, Longhi A, Ferraresi V, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol 2012;30(9):914-920.
4Casali PG, Stacchiotti S, Grosso F, et al. Adding cisplatin (CDDP) to imatinib (IM) re-establishes tumor response following secondary resistance to IM in advanced chordoma.
J Clin Oncol (Meeting Abstracts) 2007;25(18 suppl):10038.
5Stacchiotti S, Marrari A, Tamborini E, et al. Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 2009;20:1886-1894.
6Singhal N, Kotasek D, Parnis FX. Response to erlotinib in a patient with treatment refractory chordoma. Anticancer Drugs 2009;20(10):953-955.
7George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 2009;27:3154-3160.
8Stacchiotti S, Tamborini E, LoVullo S, et al. Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol 2013;24(7):1931-6.
9Amela E, Bompas E, Le Cesne A, et al. A phase II trial of sorafenib (SO) in advanced chordoma patients (pt). J Clin Oncol 2015; 33(15):Supplement 10520.
10Bompas E, Le Cesne A, Tresch-Bruneel E, et al. Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group
(GSF/GETO). Ann Oncol 2015;10:2168-2173.
11Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.
N Engl J Med 2003;348:694-701.
12Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the
Childrens Oncology Group. J Clin Oncol 2012 Nov 20;30(33):4148-54.
13Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 2001;19:1818-1829.
14Paulussen M, Craft AW, Lewis I, et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in
standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 2008;26:4385-4393.
15Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors
in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006;47:22-29.
16Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and
etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004;22:2873-2876.
17Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/
Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 2006;24:152-159.
18Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jurgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors.
Pediatr Blood Cancer 2006;47:795-800.
19Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors.
Med Pediatr Oncol 2000;35:468-474.
20Saylors RL, 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J
Clin Oncol 2001;19:3463-3469.
21Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer 2009;53:1029-
1034.
22Wagner LM, Crews KR, Iacono LC, et al. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res
2004;10:840-848.
23Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 2007;48:132-139.
24McNall-Knapp RY, Williams CN, Reeves EN, Heideman RL, Meyer WH. Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with
refractory solid tumors. Pediatr Blood Cancer 2010;54:909-915.

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25Blaney S, Berg SL, Pratt C, et al. A phase I study of irinotecan in pediatric patients: a pediatric oncology group study. Clin Cancer Res 2001;7:32-37
26Furman WL, Stewart CF, Poquette CA, et al. Direct translation of protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol
1999;17:1815-1824.
27McGregor LM, Stewart CF, Crews KR, et al. Dose escalation of intravenous irinotecan using oral cefpodoxime: A phase I study in pediatric patients with refractory solid tumors.
Pediatr Blood Cancer 2012;58:372-379.
28Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of
children and young adults. J Clin Oncol 1987;5:1191-1198.
29Magnan H, Goodbody CM, Riedel E, et al. Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma. Pediatr Blood Cancer 2015;62(4):594-7.
30Van Winkle P, Angiolillo A, Krailo M, et al. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/
refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer 2005;44:338-347.
31Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer
2008;113:419-425.
32Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res
2012;18:4415-4424.
33Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11:275-280.
34Kaiser U, Neumann K, Havemann K. Generalised giant-cell tumour of bone: successful treatment of pulmonary metastases with interferon alpha, a case report. J Cancer Res
Clin Oncol 1993;119:301-303.
35Kaban LB, Troulis MJ, Ebb D, et al. Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg 2002;60:1103-1111.
36Yasko AW. Interferon therapy for giant cell tumor of bone. Curr Opin Orthop 2006;17:568-572.
37Bramwell V, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults:
the first study of the European Osteosarcoma Intergroup. J Clin Oncol 1992;10:1579-1591.
38Lewis IJ, Nooij MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized
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39Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma
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40Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the
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41Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on
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42Bacci G, Briccoli A, Rocca M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute
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43Basaran M, Bavbek ES, Saglam S, et al. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity
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2980-2987.

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45Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue
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46Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial.
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47Le Deley MC, Guinebretiere JM, Gentet JC, et al. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate
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48Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with
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49Subbiah V; Anderson PM; Rohren E. Alpha Emitter Radium 223 in High-Risk Osteosarcoma: First Clinical Evidence of Response and Blood-Brain Barrier Penetration. JAMA
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50Anderson PM; Subbiah V; Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153-EDTMP and Radium-223. Adv Exp Med Biol
2014;804:291-304.
51Subbiah V; Rohren E; Huh WW; Kappadath CS; Anderson PM. Phase 1 dose escalation trial of intravenous radium 223 dichloride alpha-particle therapy in
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52Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an
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randomised phase 2 clinical trial. Lancet Oncol 2015;16(1):90-107.

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Table of Contents
PRINCIPLES OF RADIATION THERAPY

Patients should be strongly encouraged to have RT at the same specialized center that is providing surgical and systemic
interventions.
Specialized techniques such as intensity-modulated RT (IMRT); particle beam RT with protons, carbon ions, or other heavy ions;
stereotactic radiosurgery; or fractionated stereotactic RT should be considered as indicated in order to allow high-dose therapy
while maximizing normal tissue sparing.
CHONDROSARCOMA
Base of Skull Tumors
Postoperative therapy or RT for unresectable disease: >70 Gy with specialized techniques
Extracranial Sites
Preoperative RT (19.850.4 Gy) may be considered (if positive margins are likely) followed by individualized postoperative RT
with final target doses of 70 Gy (R1 resection)1 and 72 to 78 Gy (R2 resection).1
Postoperative RT (6070 Gy) may be considered, especially for high-grade/dedifferentiated/mesenchymal subtypes with close or
positive margins.
Consider high-dose therapy with specialized techniques for unresectable disease.
CHORDOMA
Base of Skull
Postoperative RT (R1 and R2 resection)1 or RT for unresectable disease 70 Gy or higher (total dose will depend on normal tissue
tolerance)
Consider postoperative RT for R0 resections
Mobile Spine
Consider preoperative RT (19.850.4 Gy) and postoperative RT to total dose of 70 Gy (depending on normal tissue tolerances)
1R0 = No microscopic residual disease, R1 = Microscopic residual disease, R2 = Gross residual disease
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EWING SARCOMA
Treatment of Primary Tumor
Definitive RT
Should start by week 12 of VAC/IE chemotherapy or week 18 of VIDE chemotherapy
Treatment volumes and doses:
45 Gy to initial gross tumor volume (GTV1) + 11.5 cm for clinical target volume 1 (CTV1) + 0.51 cm for planning target volume 1 (PTV1)
GTV1 defined as: pre-treatment extent of bone and soft tissue disease. If the tumor has responded to chemotherapy and normal tissues have
returned to their natural position, GTV1 should exclude pre-chemotherapy soft tissue volume that extended into a cavity
(eg, tumors indenting lung, intestine, or bladder resume normal position following chemotherapy).
Cone-down (CD) to cover original bony extent + a total of 55.8 Gy to postchemotherapy soft tissue volume (GTV2) + 11.5 cm for
CTV2 + 0.51 cm for PTV2
Consider increasing boost dose to a total of 59.4 Gy for chemotherapy response <50%
Preoperative RT
May be considered for marginally resectable tumors and is given concurrently with consolidation chemotherapy
3645 Gy for initial GTV + 2 cm
Postoperative RT
Should begin within 60 days of surgery and is given concurrently with consolidation chemotherapy
R0 resection:1 Consider treatment for poor histologic response even if margins are adequate (45 Gy to GTV2 equivalent volume +
11.5 cm for CTV1 + 0.51 cm for PTV1)
R1 resection:1 45 Gy GTV2 equivalent volume + 11.5 cm for CTV1 + 0.51 cm for PTV1
R2 resection:1 45 Gy to GTV2 equivalent volume + 11.5 cm for CTV1 + 0.51 cm for PTV1 followed by CD to residual disease plus a total of 55.8 Gy to
GTV2 + 11.5 cm for CTV2 + 0.51 cm for PTV2
Hemithorax Irradiation
Should be considered for chest wall primaries with extensive ipsilateral pleural involvement
1520 Gy (1.5 Gy/fx) followed by CD to primary site (final dose based on resection margins)
Treatment of Metastatic Disease

Whole-lung irradiation following completion of chemotherapy/metastasectomy (category 3)
15 Gy (1.5 Gy/fx) for patients <14 years
18 Gy for patients >14 years
Current Children's Oncology Group (COG) study stratifies age before or after 6 years (12 vs. 15 Gy)
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GIANT CELL TUMOR OF BONE

Consider RT (5060 Gy) for unresectable/progressive/recurrent disease that has not responded to serial embolizations, denosumab, IFN,
or PEG IFN.
An increased risk of malignant transformation following RT has been noted in some studies.
OSTEOSARCOMA
Treatment of Primary Tumor

RT should be considered for patients with positive margins of resection, subtotal resections, or unresectable disease
Postoperative RT (R1 and R2 resections):1 55 Gy with 913 Gy boost to microscopic or gross disease (total dose to high-risk
sites 6468 Gy)
Unresectable disease: 6070 Gy (total dose will depend on normal tissue tolerance)

Consider use of 153Sm-EDTMP and Radium 223
Consider use of stereotactic radiosurgery, especially for oligometastases
Note: All recommendations are category 2A unless otherwise indicated. Continue

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REFERENCES
Chondrosarcoma
Amichetti M, Amelio D, Cianchetti M, et al. A systematic review of proton therapy in the treatment of chondrosarcoma of the skull base. Neurosurg Rev 2010;33(2):155.
Goda J, Ferguson P, O'Sullivan B, et al. High-risk extracranial chondrosarcoma Long-term results of surgery and radiation therapy. Cancer 2011;117:2513-9.
Kawaguchi S, Weiss I, Lin PP, Huh WW, Lewis VO. Radiation therapy is associated with fewer recurrences in mesenchymal chondrosarcoma. Clin Orthop Relat Res 2014; 472(3): 856-864.
Rosenberg AE, Nielsen GP, Keel SB, et al. Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma.
Am J Surg Pathol 1999;23(11):1370.
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Chordoma
Amichetti M, Cianchetti M, Amelio D, et al. Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev 2009;32(4):403.
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Park L, Delaney TF, Liebsch NJ, et al. Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor.
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Yasuda M, Bresson D, Chibbaro S, Cornelius JF, Polivka M, Feuvret L, Takayasu M, George B. Chordomas of the skull base and cervical spine: clinical outcomes associated with a
multimodal surgical resection combined with proton-beam radiation in 40 patients. Neurosurg Rev 2012; 35(2):171-182; discussion 182-173.
Ewing Sarcoma
Denbo JW, Shannon Orr W, Wu Y, et al. Timing of surgery and the role of adjuvant radiotherapy in Ewing sarcoma of the chest wall: A single-institution experience.
Ann Surg Oncol 2012;19(12):3809-15.
Donaldson SS. Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 2004;42(5):471-6.
Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 2004;42(5):465-70.
Indelicato DJ, Keole SR, Lagmay JP, et al. Chest wall Ewing sarcoma family of tumors: long-term outcomes. Int J Radiat Oncol Biol Phys 2011;81(1):158-66.
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Paulino AC, Nguyen TX, Mai WY, et al. Dose response and local control using radiotherapy in non-metastatic Ewing sarcoma. Pediatr Blood Cancer 2007;49(2):145-8.
Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 2012;82(3):1142-8.
Schuck A, Ahrens S, von Schorlemer I, et al. Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials.
Int J Radiat Oncol Biol Phys 2005;63(5):1562-7.
Tanguturi SK, George S, Marcus KJ, et al. Whole lung irradiation in adults with metastatic Ewing Sarcoma: Practice patterns and implications for treatment. Sarcoma 2015, Article ID
591698 5 pages.
Yock TI, Krailo M, Fryer CJ, et al. Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group.
J Clin Oncol 2006 Aug 20;24(24):3838-43. Erratum in: J Clin Oncol 2006;24(30):4947.
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REFERENCES
Giant Cell Tumor of Bone
Caudell JJ, Ballo MT, Zagars GK, et al. Radiotherapy in the management of giant cell tumor of bone. Int J Radiat Oncol Biol Phys 2003;57(1):158.
Hug EB, Muenter MW, Adams JA, et al. 3-D-conformal radiation therapy for pediatric giant cell tumors of the skull base. Strahlenther Onkol 2002;178(5):239.
Malone S, O'Sullivan B, Catton C, et al. Long-term follow-up of efficacy and safety of megavoltage radiotherapy in high-risk giant cell tumors of bone. Int J Radiat Oncol Biol Phys
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Ruka W, Rutkowski P, Morysinski T, et al. The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone. Int J Radiat Oncol Biol Phys
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Mixed Histology Reports

DeLaney TF, Liebsch NJ, Pedlow FX, et al. Phase II study of high-dose photon/proton radiotherapy in the management of spine sarcomas. Int J Radiat Oncol Biol Phys 2009;74(3):732-9.
Jingu K, Tsujii H, Mizoe JE, Hasegawa A, Bessho H, Takagi R, Morikawa T, Tonogi M, Tsuji H, Kamada T, Yamada S. Organizing Committee for the Working Group for Head-and-Neck
Cancer. Carbon ion radiation therapy improves the prognosis of unresectable adult bone and soft-tissue sarcoma of the head and neck. Int J Radiat Oncol Biol Phys 2012; 82(5): 2125-
2131.
Kamada T, Tsujii H, Yanagi T, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. Working Group for the Bone and Soft Tissue Sarcomas. J Clin Oncol
2002;20(22):4466.
Wagner TD, Kobayashi W, Dean S, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of
tumors involving the bone. Int J Radiat Oncol Biol Phys 2009;73(1):259-66.
Osteosarcoma
Anderson PM; Subbiah V; Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153-EDTMP and Radium-223. Adv Exp Med Biol 2014;804:291-
304.
Ciernik IF, Niemierko A, Harmon DC, Kobayashi W, Chen YL, Yock TI, Ebb DH, Choy E, Raskin KA, Liebsch N, Hornicek FJ, Delaney TF. Proton-based radiotherapy for unresectable or
incompletely resected osteosarcoma. Cancer 2011;117(19): 4522-4530.
DeLaney, TF, Park L, Goldberg SI, Hug EB, Liebsch NJ, Munzenrider JE, Suit HD. Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 2005;61(2): 492-498.
Guadagnolo BA, Zagars GK, Raymond AK, Benjamin RS, Sturgis EM. Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Cancer 2009;115(14): 3262-
3270.
Mahajan A, Woo SY, Kornguth DG, Hughes D, Huh E, Chang EL, Herzog CE, Pelloski CE, Anderson P. Multimodality treatment of osteosarcoma: radiation in a high-risk cohort. Pediatr
Blood Cancer 2008;50(5): 976-982.
Subbiah V; Anderson PM; Rohren E. Alpha Emitter Radium 223 in High-Risk Osteosarcoma: First Clinical Evidence of Response and Blood-Brain Barrier Penetration. JAMA Oncol
2015;1(2):253-255.
Subbiah V; Rohren E; Huh WW; Kappadath CS; Anderson PM. Phase 1 dose escalation trial of intravenous radium 223 dichloride alpha-particle therapy in osteosarcoma. J Clin Oncol
2014;32(5s): Abstract TPS10600. Presented at the 2014 ASCO Annual Meeting, Chicago, IL, United States.

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NCCN Guidelines Version 2.2017 Staging NCCN Guidelines Index

Table of Contents
Table 1 Stage Grouping

Stage IA T1 N0 M0 G1, 2 Low grade, GX
American Joint Committee on Cancer (AJCC) Stage IB T2 N0 M0 G1, 2 Low grade, GX
TNM Staging System for Bone (Primary malignant lymphoma and T3 N0 M0 G1, 2 Low grade, GX
multiple myeloma are not included) Stage IIA T1 N0 M0 G3, 4 High grade
Stage IIB T2 N0 M0 G3, 4 High grade
(7th ed., 2010)
Primary Tumor (T) Stage III T3 N0 M0 G3
TX Primary tumor cannot be assessed Stage IVA Any T N0 M1a Any G
T0 No evidence of primary tumor Stage IVB Any T N1 Any M Any G
T1 Tumor 8 cm or less in greatest dimension Any T Any N M1b Any G
T2 Tumor more than 8 cm in greatest dimension Used with the permission of the American Joint Committee on Cancer (AJCC),
T3 Discontinuous tumors in the primary bone site Chicago, Illinois. The original and primary source for this information is the
AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer
Regional Lymph Nodes (N)
Science+Business Media, LLC (SBM). (For complete information and data
NX Regional lymph nodes cannot be assessed
supporting the staging tables, visit www.springer.com.) Any citation or quotation
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis of this material must be credited to the AJCC as its primary source. The
inclusion of this information herein does not authorize any reuse or further
Note: Because of the rarity of lymph node involvement in bone distribution without the expressed, written permission of Springer SBM, on
sarcomas, the designation NX may not be appropriate and behalf of the AJCC.
cases should be considered N0 unless clinical node
Table 2
involvement is clearly evident.
Surgical Staging System (SSS)
Distant Metastasis (M)
M0 No distant metastasis Stage Grade Site
M1 Distant metastasis IA Low (G1) Intracompartmental (T1)
M1a Lung
IB Low (G1) Extracompartmental (T2)
M1b Other distant sites
IIA High (G2) Intracompartmental (T1)
Histologic Grade (G) IIB High (G2) Extracompartmental (T2)
GX Grade cannot be assessed
III Any (G) + Any (T)
G1 Well differentiated Low Grade
G2 Moderately differentiated Low Grade Regional or
G3 Poorly differentiated distant metastasis
G4 Undifferentiated From Enneking WF, Spanier SS, Goodman MA: A system for the surgical
Note: Ewing's sarcoma is classified as G4. staging of musculoskeletal sarcoma. Clin Orthop 1980:153:106-120.

ST-1

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Relapsed Disease ............................................................................... MS-8

Discussion
Chordoma .............................................................................................. MS-8
NCCN Categories of Evidence and Consensus Workup ................................................................................................ MS-9
Treatment ............................................................................................ MS-9
Category 1: Based upon high-level evidence, there is uniform NCCN
Surveillance ...................................................................................... MS-11
consensus that the intervention is appropriate.
Relapsed Disease ............................................................................. MS-11
Category 2A: Based upon lower-level evidence, there is uniform
Ewing Sarcoma ................................................................................... MS-11
NCCN consensus that the intervention is appropriate.
Prognostic Factors ............................................................................ MS-12
Category 2B: Based upon lower-level evidence, there is NCCN Workup .............................................................................................. MS-13
consensus that the intervention is appropriate. Treatment .......................................................................................... MS-13
Category 3: Based upon any level of evidence, there is major NCCN Surveillance ...................................................................................... MS-16
disagreement that the intervention is appropriate. Relapsed or Refractory Disease........................................................ MS-16
All recommendations are category 2A unless otherwise noted. Giant Cell Tumor of Bone ................................................................... MS-18
Workup .............................................................................................. MS-18
Table of Contents Treatment .......................................................................................... MS-18
Overview ................................................................................................ MS-2 Surveillance ...................................................................................... MS-20
Literature Search Criteria and Guidelines Update Methodology ....... MS-3 Osteosarcoma ..................................................................................... MS-20
Staging ................................................................................................... MS-3 Prognostic Factors ............................................................................ MS-21
Principles of Bone Cancer Management ............................................. MS-3 Workup .............................................................................................. MS-22
Multidisciplinary Team Involvement ..................................................... MS-3 Treatment .......................................................................................... MS-22
Diagnostic Workup............................................................................... MS-3 Localized Disease ............................................................................. MS-23
Biopsy .................................................................................................. MS-4 Metastatic Disease at Presentation ................................................... MS-24
Surgery ................................................................................................ MS-5 Surveillance ...................................................................................... MS-25
Radiation Therapy ............................................................................... MS-5 Relapsed or Refractory Disease........................................................ MS-25
Chondrosarcoma ................................................................................... MS-5 High-grade Undifferentiated Pleomorphic Sarcoma of Bone .......... MS-27
Prognostic Factors ............................................................................... MS-6 Summary ............................................................................................. MS-27
Treatment ............................................................................................ MS-6 References .......................................................................................... MS-29
Surveillance ......................................................................................... MS-8
Version 2.2017, 11/07/2016 National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-1

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Overview osteosarcoma.10,11 Li-Fraumeni syndrome characterized by a germline

mutation in the TP53 gene is associated with a high risk of developing
Primary bone cancers are extremely rare neoplasms accounting for
osteosarcoma.12-14 Osteosarcoma is the most common second primary
less than 0.2% of all cancers, although the true incidence is difficult to
malignancy in patients with a history of retinoblastoma, characterized
determine secondary to the rarity of these tumors.1 In 2016, an
by a mutation in the retinoblastoma gene RB1.10,15,16 Increased
estimated 3300 people will be diagnosed in the United States and 1490
incidences of osteosarcoma have also been associated with other
people will die from the disease.2 Primary bone cancers demonstrate
inherited genetic predisposition syndromes characterized by mutations
wide clinical heterogeneity and are often curable with proper treatment.
in the DNA helicase genes.10 Osteosarcoma is also the most common
Osteosarcoma (35%), chondrosarcoma (30%), and Ewing sarcoma
radiation-induced bone sarcoma.17,18
(16%) are the three most common forms of bone cancer. High-grade
undifferentiated pleomorphic sarcoma (UPS) of bone, fibrosarcoma, The development of multiagent chemotherapy regimens for
chordoma, and giant cell tumor of bone (GCTB) are relatively rare neoadjuvant and adjuvant treatment has considerably improved the
tumors constituting up to 1% to 5% of all primary malignant bone prognosis for patients with osteosarcoma and Ewing sarcoma.19,20 With
tumors.3 GCTB has both benign and malignant forms, with the benign current multimodality treatment, approximately three quarters of all
form being the most common subtype. patients diagnosed with osteosarcoma are cured and 90% to 95% of
patients diagnosed with osteosarcoma can be successfully treated with
Various types of bone cancers are named based on their histologic limb-sparing approaches rather than amputation.21 Survival rates have
origin: chondrosarcomas arise from cartilage, osteosarcomas arise improved to almost 70% in patients with localized Ewing sarcoma.20 In
from bone, and fibrogenic tissue is the origin of fibrosarcoma of bone, patients with Ewing sarcoma and osteosarcoma, a cure is still
whereas vascular tissue gives rise to hemangioendothelioma and achievable in selected patients diagnosed with metastatic disease at
hemangiopericytoma. Notochordal tissue gives rise to chordoma. presentation.22,23 The 5-year survival across all types of primary bone
Several primary bone cancers, including Ewing sarcoma, are of cancers is 66.6%.1
unknown histologic origin. Chondrosarcoma is usually found in
middle-aged and older adults. Osteosarcoma and Ewing sarcoma The NCCN Guidelines for Bone Cancer focus on chordoma,
develop mainly in children and young adults. Chordoma is more chondrosarcoma, Ewing sarcoma, and osteosarcoma. The guidelines
common in males, with the peak incidence in the fifth to sixth decades also provide recommendations for treating GCTB. Although typically
of life.4,5 benign, GCTB is locally aggressive and can lead to significant bone
destruction.
The pathogenesis and etiology of most bone cancers remain unclear.
Gene rearrangements between the EWS and ETS family of genes have
been implicated in the pathogenesis of Ewing sarcoma.6-9 Specific
germline mutations have also been implicated in the pathogenesis of

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Literature Search Criteria and Guidelines Update and/or distant metastases (M).24 The Surgical Staging System is
Methodology another staging system for bone and soft tissue sarcomas developed
Prior to the update of this version of the NCCN Guidelines for Bone by the Musculoskeletal Tumor Society (Table 2).25 This system stratifies
Cancer, an electronic search of the PubMed database was performed both bone and soft tissue sarcomas by the assessment of the surgical
to obtain key literature in bone cancer published between May 2015 grade (G), local extent (T), and presence or absence of regional or
and May 2016, using the following search terms: chondrosarcoma OR distant metastases. It may be used in addition to the AJCC staging
chordoma OR Ewing sarcoma OR giant cell tumor of the bone OR system.
osteosarcoma OR bone sarcoma OR primary bone cancer OR primary
bone neoplasm OR primary bone tumor. The PubMed database was Principles of Bone Cancer Management
chosen as it remains the most widely used resource for medical Multidisciplinary Team Involvement
literature and indexes only peer-reviewed biomedical literature. Primary bone tumors and selected metastatic tumors should be
evaluated and treated by a multidisciplinary team of physicians with
The search results were narrowed by selecting studies in humans
demonstrated expertise in the management of these tumors. Long-term
published in English. Results were confined to the following article
surveillance and follow-up are necessary when considering the risk of
types: Clinical Trial; Guideline; Randomized Controlled Trial; Meta-
recurrence and comorbidities associated with chemotherapy and
Analysis; Systematic Reviews; and Validation Studies.
radiation therapy (RT). Life-long follow-up is recommended for
The PubMed search resulted in 159 citations and their potential surveillance and treatment of late effects of surgery, RT, and
relevance was examined. The data from key PubMed articles as well as chemotherapy in long-term survivors. Patients should be given a
articles from additional sources deemed as relevant to these guidelines survivorship prescription to schedule follow-up with a multidisciplinary
and discussed by the panel have been included in this version of the team. Fertility issues should be discussed with appropriate patients.26
Discussion section (eg, e-publications ahead of print, meeting For information on disease- and survivorship-related issues for
abstracts). Recommendations for which high-level evidence is lacking adolescent and young adult patients, please refer to the NCCN
are based on the panels review of lower-level evidence and expert Guidelines for Adolescent and Young Adult (AYA) Oncology as
opinion. clinically appropriate.
The complete details of the Development and Update of the NCCN Diagnostic Workup
Guidelines are available at www.NCCN.org. Suspicion of a malignant bone tumor in a patient with a symptomatic
lesion often begins when a poorly marginated lesion is seen on a plain
Staging radiograph. In patients younger than 40 years, an aggressive,
The 2010 AJCC staging classification is based on the assessment of symptomatic bone lesion has a significant risk of being a malignant
histologic grade (G), tumor size (T), and presence of regional (N) primary bone tumor, and referral to an orthopedic oncologist should be

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considered prior to further workup. In patients 40 years of age and Biopsy

older, CT scan of the chest, abdomen, and pelvis; bone scan; Incisional (open) biopsy and percutaneous biopsy (core needle or fine-
mammogram; and other imaging studies as clinically indicated should needle aspiration [FNA]) are the two techniques historically used in the
be performed if plain radiographs do not suggest a specific diagnosis.27 diagnosis of musculoskeletal lesions.38,39 Open biopsy is the most
accurate method because of larger sample size, which is useful for
All patients with suspected bone sarcoma should undergo complete
performing additional studies such as immunohistochemistry or
staging prior to biopsy. The standard staging workup for a suspected
cytogenetics.40 However, open biopsy requires general or regional
primary bone cancer should include chest imaging (chest radiograph or
anesthesia and an operating room, whereas core biopsy can be
chest CT to detect pulmonary metastases), appropriate imaging of the
performed under local anesthesia, with or without sedation. Core
primary site (plain radiographs, MRI for local staging, and/or CT scan),
needle biopsy has also been used as an alternative to open biopsy for
and bone scan.28 Whole-body MRI is a sensitive imaging technique for
the diagnosis of musculoskeletal lesions with accuracy rates ranging
the detection of skeletal metastases in patients with small cell
from 88% to 96% when adequate samples are obtained.41-44 Cost
neoplasms, Ewing sarcoma, and osteosarcoma.29,30 Imaging of painless
savings may be realized when needle biopsy is employed in selected
bone lesions should be evaluated by a musculoskeletal radiologist
patients.41 Recent advances in imaging techniques have contributed to
followed by appropriate referral to a multidisciplinary treatment team if
the increasing use of image-guided percutaneous biopsy for the
necessary. Laboratory studies, such as complete blood count (CBC),
diagnosis of primary and secondary bone tumors.45 The method of
lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) should
choice for biopsy remains controversial since no randomized controlled
be done prior to initiation of treatment.
trials have compared core needle biopsy with open biopsy.
PET/CT is an alternative imaging technique that has been utilized in the
The guidelines recommend core needle or open biopsy to confirm the
pretreatment staging of soft tissue and bone sarcomas.31,32 Recent
diagnosis of primary bone tumor prior to any surgical procedure or
reports in literature have demonstrated the utility of PET scans in the
fixation of primary site. Biopsy should be performed at the center that
evaluation of response to chemotherapy in patients with osteosarcoma,
will provide definitive treatment for patients with a suspected primary
Ewing sarcoma, and advanced chordoma.33-36 PET/CT with the
malignant bone tumor. At the time of biopsy, careful consideration
investigational radioactive substance 18F-fluoromisonidazole (FMISO)
should be given to appropriate stabilization of the bone and/or
has been shown to identify the hypoxic component in residual
measures to protect against impending pathologic fracture. The
chordomas prior to RT.37 This approach is being evaluated in clinical
placement of biopsy is critical to the planning of limb-sparing surgery,
trials and would be helpful in identifying tumors with low oxygen levels
and failure to follow appropriate biopsy procedures may lead to adverse
that are more resistant to RT.
patient outcomes.38,39 In a multicenter review of 597 patients with
musculoskeletal tumors, alteration of the treatment plan (complex
resection or the use of adjunctive treatment) was encountered in 19%

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of patients and unnecessary amputation was performed in 18 evaluate for mobility training and to prescribe an appropriate
patients.46 rehabilitation program.
Both open and core needle biopsy techniques are associated with risk Radiation Therapy
of local tumor recurrence either by tumor spillage or tumor seeding RT is used either as an adjuvant to surgery for patients with resectable
along the biopsy tract, if the scar is not removed en bloc during the tumors or as definitive therapy in patients with tumors not amenable to
tumor resection. The risk of tumor seeding is less with core needle surgery. Specialized techniques such as intensity-modulated RT
biopsy.47,48 Nevertheless, the same principles should be applied for core (IMRT); particle beam RT with protons, carbon ions, or other heavy
needle and open biopsy. Appropriate communication between the ions; stereotactic radiosurgery (SRS); or fractionated SRS (FSRT)
surgeon, musculoskeletal oncologist, and bone pathologist is critical in should be considered as clinically indicated in order to deliver high
planning the biopsy route. It is essential to select the biopsy route in radiation doses while maximizing normal tissue sparing.50,51 RT should
collaboration with the surgeon to ensure that the biopsy tract lies within be administered at the same specialized center that is providing
the planned resection bed so that it can be resected with the same wide surgical and systemic interventions. See Principles of Radiation
margins as the primary tumor during surgery. Although the risk of tumor Therapy in the guidelines algorithm for treatment volumes and radiation
seeding is not significant with FNA biopsy, it is not suitable for the doses specific to each subtype.
diagnosis of primary lesions since the diagnostic accuracy of FNA is
less than that of core needle biopsy.49 Chondrosarcoma
Chondrosarcomas characteristically produce cartilage matrices from
Surgery
neoplastic tissue devoid of osteoid and may occur at any age, but they
Surgical margins should be negative, wide enough to minimize potential are more common in older adults.52,53 The pelvis and the proximal femur
local recurrence, and narrow enough to maximize function. Wide are the most common primary sites. Conventional chondrosarcoma of
excision implies histologically negative surgical margins and it is the bone constitutes approximately 85% of all chondrosarcomas and is
necessary to optimize local control. Local control may be achieved divided as follows: 1) primary or central lesions arising from previously
either by limb-sparing surgery or amputation. In selected cases, normal-appearing bone preformed from cartilage; or 2) secondary or
amputation may be the most appropriate option to achieve this goal. peripheral tumors that arise or develop from preexisting benign
However, limb-sparing surgery is preferred if reasonable functional cartilage lesions, such as enchondromas, or from the cartilaginous
outcomes can be achieved. Final pathologic evaluation should include portion of an osteochondroma.52,54 Malignant transformation has been
assessment of surgical margins and size/dimensions of tumor. The reported in patients with Olliers disease (enchondromatosis) and
response to the preoperative therapy should be evaluated utilizing Maffucci syndrome (enchondromatosis associated with soft tissue
pathologic mapping. Consultation with a physiatrist is recommended to hemangioma).55 The peripheral or secondary tumors are usually low
grade with infrequent metastasis.56 About half of chondrosarcoma

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cases and nearly all cases of Olliers disease and Maffucci syndrome later in the disease course, as the associated pain has a more insidious
are related to isocitrate dehydrogenase (IDH1 or IDH2) mutations.57-59 onset and often occurs when the tumor has reached a significant
size.67-69 Central chondrosarcomas demonstrate cortical destruction and
In addition to conventional chondrosarcoma, there are several other loss of medullary bone trabeculations on radiographs, as well as
rare subtypes constituting about 10% to 15% of all chondrosarcomas.52 calcification and destruction.68 MRI will show the intramedullary
These include clear cell, dedifferentiated, myxoid, and mesenchymal involvement as well as extraosseous extension of the tumor. Secondary
forms of chondrosarcoma.52,60 Primary skeletal myxoid chondrosarcoma lesions arise from preexisting lesions. Serial radiographs will
(myxoid chondrosarcoma of bone) is an extremely rare neoplasm that demonstrate a slow increase in size of the osteochondroma or
has not been fully characterized as a distinct clinicopathologic entity.61,62 enchondroma. A cartilage cap measuring greater than two
It is considered to be a myxoid variant of intermediate- or high-grade centimeters on a pre-existing lesion or documented growth after
chondrosarcoma and is commonly located in the bones around the hip skeletal maturity should raise the suspicion of sarcomatous
joint.52,62 Research suggests that alterations in the retinoblastoma transformation.70
pathway are present in a significant majority of clear cell,
dedifferentiated, and mesenchymal chondrosarcomas.60 Prognostic Factors
Whether the lesion is primary or secondary, central or peripheral, the
Extraskeletal myxoid chondrosarcoma, on the other hand, is a rare soft
anatomic location, histologic grade, and size of the lesion are essential
tissue sarcoma that is characterized by chromosomal translocations
prognostic features.67,71-75 In an analysis of 2890 patients with
t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating the fusion genes,
chondrosarcoma from the SEER database, female sex, a low histologic
EWS-CHN (EWSR1-NR4A3) or RBP56-CHN (TAF2N-NR4A3),
grade, and local surgical stage were associated with a significant
respectively.63,64 In addition, two other variant chromosomal
disease-specific survival benefit in the univariate analysis, whereas only
translocations, t(9;15)(q22;q21) and t(3;9)(q12;q22), resulting in fusion
grade and stage had significant association with disease-specific
genes, TCF12-NR4A3 and TFG-NR4A3, respectively, have also been
survival on multivariate analysis.76
identified in case reports.65 A recent retrospective study demonstrated
prolonged overall survival (OS) in patients with extraskeletal myxoid Treatment
chondrosarcoma despite high rates of local and distant recurrence.66
Surgery
The data also revealed a significant pattern of decreased event-free
Wide excision with negative margins is the preferred primary treatment
survival (EFS) with increasing tumor size. Extraskeletal myxoid
for patients with large tumors and pelvic localization, irrespective of the
chondrosarcoma is not included in the NCCN Guidelines for Bone
grade.73,77-79 Wide resection with adequate surgical margins is
Cancer.
associated with higher EFS and OS rates in patients with
Symptoms of chondrosarcoma are usually mild and depend on tumor chondrosarcoma of axial skeleton and pelvic girdle. The 10-year OS
size and location. Patients with pelvic or axial lesions typically present and EFS rates were 61% and 44%, respectively, for patients who

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underwent resection with adequate surgical margins compared to the combination of proton and photon beam RT resulted in 10-year local
corresponding survival rates of 17% and 0% for those who underwent control rates of 94%.90 Carbon ion RT has also been reported to result
resection with inadequate surgical margins.80 Intralesional curettage in high local control rates in patients with skull base chondrosarcoma.97-
with adjuvant cryosurgery has been shown to be associated with low 99
Recently, SRS has also been evaluated for adjuvant treatment of
rates of recurrence in patients with grade I intracompartmental skull base chondrosarcoma.100
chondrosarcomas.81-83 In selected patients with low-grade and less
radiographically aggressive, non-pelvic chondrosarcomas, intralesional Chemotherapy
excision can be used as an alternative to wide excision without Chemotherapy is generally not effective in chondrosarcoma, particularly
compromising outcomes.84-86 This approach should be restricted to the conventional and dedifferentiated subtypes. Mitchell and colleagues
extremity tumors. reported that adjuvant chemotherapy with cisplatin and doxorubicin was
associated with improved survival in patients with dedifferentiated
Radiation Therapy chondrosarcoma.101 However, this finding could not be confirmed in
RT can be considered after incomplete resection or for palliation of other studies.102-104 A recent review of outcomes for 113 patients with
symptoms in patients with advanced or unresectable tumors.52,53 In a mesenchymal chondrosarcoma reported that the addition of
retrospective analysis of 60 patients who underwent surgery for chemotherapy was associated with reduced risk of recurrence and
extracranial high-risk chondrosarcoma, the use of RT as an adjunct to death.105 Another report from the German study group also confirmed
surgery (preoperative or postoperative) was associated with excellent that the outcome was better in younger patients with mesenchymal
and durable local control for tumors not amenable to wide surgical chondrosarcoma who received chemotherapy.106 In the absence of data
resection.87 A recent retrospective study of patients with mesenchymal from prospective randomized trials, the role of chemotherapy in the
chondrosarcoma suggested that adjuvant RT for local tumor control treatment of chondrosarcomas remains undefined.
was associated with fewer recurrences.88
NCCN Recommendations
Proton beam RT alone or in combination with photon beam RT has The histologic grade and tumor locations are the most important
been associated with an excellent local tumor control and long-term variables that determine the choice of the primary treatment.
survival in the treatment of patients with low-grade skull base and
cervical spine chondrosarcomas.89-96 In two separate studies, proton Wide excision or intralesional excision with or without an adjuvant are
beam RT resulted in local control rates of 92% and 94% in patients with the primary treatment options for patients with resectable low-grade
chondrosarcoma of the skull base.89,93 Noel et al reported a 3-year local and intracompartmental lesions.85,86 Wide excision is the preferred
control rate of 92% in 26 patients with chondrosarcoma of the skull treatment option for patients with pelvic low-grade chondrosarcomas.77
base and upper cervical spine treated with surgical resection followed High-grade (grade II, III), clear cell, or extracompartmental lesions, if
by a combination of proton and photon beam RT.92 In a larger series resectable, should be treated with wide excision obtaining negative
involving 229 patients with chondrosarcomas of the skull base, the surgical margins.80 Wide excision should provide negative surgical

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margins and may be achieved by either limb-sparing surgery or Relapsed Disease

amputation. Local recurrence should be treated with wide excision if the lesions are
resectable. RT (category 2B) or re-resection to achieve negative
Postoperative treatment with proton and/or photon beam RT may be
surgical margins should be considered following wide excision with
useful for patients with tumors in an unfavorable location not amenable
positive surgical margins. Negative surgical margins should be
to resection, especially in chondrosarcomas of the skull base and axial
observed. Unresectable recurrences are treated with RT. A recent
skeleton.52,53 RT can be considered for patients with unresectable high-
study in 25 patients demonstrated effective local control and low acute
and low-grade lesions. However, since there are not enough data to
toxicity with carbon ion RT in patients with recurrent skull base
support the use of RT in patients with chondrosarcoma, the panel has
chordoma or chondrosarcoma.107 Surgical excision or participation in a
included this option with a category 2B recommendation.
clinical trial (preferred) could be considered for patients with systemic
There are no established chemotherapy regimens for conventional recurrence of a high-grade chondrosarcoma.
chondrosarcoma (grades 13). The guidelines suggest that patients
with dedifferentiated chondrosarcomas could be treated as per
Chordoma
osteosarcoma and those with mesenchymal chondrosarcomas could be Chordomas arise from the embryonic remnants of the notochord and
treated as per Ewing sarcoma. Both of these options are included with are more common in older adults. Chordomas predominantly arise in
a category 2B recommendation. the axial skeleton, with the sacrum (50%60%), skull base (25%35%),
and spine (15%) being the most common primary sites.5,108 Chordomas
Surveillance are classified into three histologic variants: conventional, chondroid,
Surveillance for low-grade lesions consists of a physical exam: imaging and dedifferentiated. Conventional chordomas are the most common
of the chest and primary site every 6 to 12 months for 2 years and then histologic subtype characterized by the absence of cartilaginous or
yearly as appropriate. mesenchymal components. Chondroid chordomas present with
histologic features of chordoma and cartilage elements, accounting for
Surveillance for high-grade lesions consists of a physical exam, 5% to 15% of all chordomas. Dedifferentiated chordomas constitute
radiographs of the primary site, and/or cross-sectional imaging (MRI or about 2% to 8% of all chordomas and have features of high-grade
CT) as clinically indicated as well as chest imaging based on pleomorphic spindle cell soft tissue sarcoma and an aggressive clinical
physicians concern for risk of recurrence. Chest imaging should occur course.108
every 3 to 6 months (may include CT at least biannually) for the first 5
years and yearly thereafter for a minimum of 10 years, as late Chordomas of the spine and sacrum present with localized deep pain
metastases and recurrences after 5 years are more common with or radiculopathies, whereas cervical chordomas can cause airway
chondrosarcoma than with other sarcomas.72 Functional assessment obstruction or dysphagia and might present as an oropharyngeal mass.
should be performed at every visit. Neurologic deficit is more often associated with chordomas of the skull

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base and mobile spine than chordomas of sacrococcygeal region.5 A Biopsy to confirm histologic subtype should be done after imaging
review of 47 patients with skull base chordomas suggested that male studies and may vary depending on the anatomic location of the tumor.
sex was associated with worse progression-free survival (PFS) and Needle biopsy is not recommended for skull base tumors. Suspected
OS.109 sacral chordomas should be biopsied dorsally rather than transrectally.
Workup Treatment
Initial workup should include history and physical examination with Surgery
adequate imaging (x-ray, CTMRI) of the primary site, screening MRI of Wide excision with adequate margins is the preferred primary treatment
spinal axis, and CT scan of the chest, abdomen, and pelvis. PET/CT for patients with chordoma.121,122 A recent retrospective analysis of 962
scan or bone scan (if PET scan is negative) can be considered for patients with chordoma identified in the SEER database demonstrated
unusual cases. Benign notochordal cell tumors (BNCTs) are considered that surgery significantly improves OS.122 Several other reports have
precursors to chordomas and do not require surgical management.110,111 confirmed the prognostic significance of wide surgical margins, in terms
CT scan and MRI may be useful in distinguishing BNCTs from of relapse-free survival (RFS) and OS, in patients with chordomas of
chordomas.112,113 the sacrum,123-126 skull base,127-132 and spine.125,133,134 Among patients
with chordoma of the mobile spine, Boriani et al reported that only
For skull base chordomas, CT is useful to delineate bone destruction margin-free en bloc resection was associated with continuous
and the presence of calcifications, whereas MRI is the modality of disease-free survival (DFS) with a follow-up of longer than 5 years; 12
choice to define the tumor margin from brain, characterization of the of 18 patients were continuously disease-free at an average of 8 years
position and extension of tumors into the adjacent soft tissue structures, after en bloc resection, whereas all patients who were treated with
and visualization of blood vessels.114,115 For sacrococcygeal chordomas, intralesional excision experienced recurrences in fewer than 2 years.133
CT and MRI are useful to assess the soft tissue involvement, In patients with chordomas of the sacrum and spine, Ruggieri et al
calcifications, and epidural extension.116-118 MRI provides more precise reported a local recurrence rate of only 17% following wide surgical
and superior contrast with surrounding soft tissues compared with CT margins compared to 81% following intralesional excision or marginal
and is helpful to assess recurrent or metastatic lesions.116,117 CT is also surgery. Tzortzidis et al reported that aggressive microsurgical
of particular importance to assess bony involvement, calcifications, and resection is associated with long-term, tumor-free survival with good
soft tissue and epidural extension of spinal chordomas, whereas MRI is functional outcome in patients with cranial base chordomas; gross total
the best imaging modality to detect tumor extension, cord compression, removal was achieved in 72% of patients resulting in local control rates
local recurrence, and residual tumor in the surgical scar tissue after of 50%.128 In a recent 10-year meta-analysis that included 802 patients
surgical resection.119,120 CT scan is also useful in planning the with skull base chordoma, Di Maio et al reported that patients with
reconstruction of the resistant osseous defect in tumors of the proximal incomplete resection were 3.83 times more likely to experience a
sacrum. recurrence at 5 years than patients with complete resection.131,132

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Radiation Therapy Specialized techniques such as IMRT, SRS, and FSRT have also been
RT (preoperative, postoperative, or intraoperative) is used in associated with good local control rates in cranial as well as
combination with surgery to improve local control and DFS for patients extracranial chordomas.96,154-158
with resectable chordomas. Various retrospective studies and case
series have demonstrated improved local control and DFS with Systemic Therapy
combined surgical/RT approaches for treating spinal/sacral95,135-138 and Chordomas are not sensitive to chemotherapy except for the potentially
clival/skull base chordomas.127,137,139-142 dedifferentiated portion of high-grade dedifferentiated chordomas.159
Several signal transduction pathways including platelet-derived growth
A meta-analysis of 464 patients with cranial chordoma revealed a factor receptor (PDGFR), epidermal growth factor receptor (EGFR),
recurrence rate of 68% with an average/median DFS of 23 and 45 and mammalian target of rapamycin (mTOR) have been implicated in
months, respectively.141 Patient subsets with decreased recurrence the pathogenesis of chordomas, leading to the development of targeted
rates included younger patients, those with chondroid-type chordoma, therapies.160,161
and patients who received surgery and adjuvant RT.
In a phase II trial of 56 patients with advanced chordoma treated with
Particle beam RT (either alone or in combination with photon beam RT) imatinib, a tyrosine kinase inhibitor, 70% of patients had stable disease.
with high-energy protons89-92,95,136,142-148 or carbon ions97,98,149-153 has The clinical benefit rate (CBR) as determined by RECIST criteria
resulted in local control rates ranging from 62% to 81% in patients with (complete response + partial response and stable disease 6 months)
skull base as well as extracranial chordomas involving the spine and was 64%, and the median PFS in the intention-to-treat population was
sacrum. Carbon ion RT also resulted in preservation of 9 months.36 Imatinib in combination with cisplatin or sirolimus has also
urinary-anorectal function compared with surgery in patients with sacral been effective in a small series of patients with advanced chordoma
chordomas.151 resistant to prior imatinib therapy.162,163 A recent retrospective study of
imatinib in advanced, progressive, and inoperable chordoma achieved
A recent prospective trial of high-dose photon/proton RT in 50 patients stable disease in 74% of patients, with a median PFS of 9.9
with bone sarcomas of the spine (n = 29 chordoma, 14 months.164The efficacy of EGFR inhibitors such as erlotinib and
chondrosarcoma, 7 other histologies) resulted in 5- and 8-year actuarial lapatinib has also been demonstrated in patients with advanced
local control rates of 94% and 85% for primary tumors and 81% and chordoma resistant to imatinib.165-167 In a phase II study of 18 patients
74% primary and locally recurrent tumors. The 8-year actuarial risk of with locally advanced and metastatic chordoma, lapatinib induced
grades 3-4 RT toxicity was 13%.95 A subsequent retrospective review of partial response in 33% of patients and 39% of patients had stable
126 patients with spinal/sacral chordoma who received high-dose disease, based on Choi response criteria, whereas all patients had
proton therapy revealed 5-year OS and local control of 81% and 62%, stable disease based on RECIST criteria.167 The median PFS was 6
respectively.136 months and 8 months (with a CBR of 22%) based on Choi and RECIST
criteria, respectively.

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In the most recent update of the guidelines, the multikinase inhibitor 6 months for 5 years and annually thereafter; may include CT annually),
sorafenib was added as a systemic therapy option based on data from and annual cross-sectional abdominal imaging.
a phase II trial in 27 patients with advanced/metastatic chordoma. In
this trial, the intent-to-treat best objective response was 1/27 (3.7%; Relapsed Disease
95% CI, 0.1%19.0%), 9-month PFS was 73.0% (95% CI, 46.188.0) Chordomas are characterized by a high rate of local recurrence and
and a 12-month OS was 86.5% (95% CI, 55.896.5).168,169 distant metastases to lungs, bone, soft tissue, lymph nodes, liver, and
skin have been reported in up to 40% of patients with local
NCCN Recommendations recurrence.123,143,172,173 Among patients with recurrent chordomas of skull
Tumor location is the most important variable that determines the base and spine, Fagundes et al reported a higher 2-year actuarial OS
choice of primary treatment for patients with conventional or chondroid rate for patients treated with subtotal resection than those who received
chordomas. Dedifferentiated chordomas are usually managed as supportive care only (63% and 21%, respectively; P = .001).143
described in the NCCN Guidelines for Soft Tissue Sarcoma. However, some studies have reported that surgery and RT are
associated with lower local control rates for recurrent tumors than for
Wide excision with or without RT is the primary treatment option for
primary tumors in patients with sacral chordomas.145,156 A recent study
patients with resectable conventional or chondroid chordomas of the
in 25 patients demonstrated effective local control and low acute toxicity
sacrum and mobile spine.121,122 Intralesional excision with or without RT
with carbon ion RT in patients with recurrent skull base chordoma or
(followed by MRI to assess the adequacy of resection) is the treatment
chondrosarcoma.107
of choice for patients with resectable skull base tumors of conventional
or chondroid histology. Maximal safe resection is recommended when Patients with recurrent disease can be managed with surgery and/or
appropriate.130 Adjuvant treatment with RT can be considered for large RT and/or systemic therapy. The guidelines have included imatinib with
extracompartmental tumors or for positive surgical margins following or without cisplatin or sirolimus, erlotinib, sunitinib, and lapatinib (for
resection. Postoperative RT has been associated with improved local patients with EGFR-positive disease) as systemic therapy options for
control and DFS following surgery with macroscopic surgical margins or patients with recurrent tumors.
intralesional excision.135,137,141,170,171 Re-resection, if necessary, can be
considered for skull base tumors with positive surgical margins. Ewing Sarcoma
Ewing sarcoma is characterized by the fusion of the EWS gene
RT is the primary treatment option for patients with unresectable
(EWSR1) on chromosome 22q12 with various members of the ETS
chordomas, irrespective of the location of the tumor.
gene family (FLI1, ERG, ETV1, ETV4, and FEV).7,8 The EWS-FLI1
Surveillance fusion transcript resulting from the fusion of EWS and FLI1 on
Surveillance consists of a physical exam, imaging (ie, x-ray, CT with or chromosome 11 and the corresponding chromosomal translocation,
without MRI) of surgical site as clinically indicated, chest imaging (every t(11;22)(q24;q12), is identified in about 85% of patients with Ewing

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sarcoma.7 In 5% to 10% of cases, EWS is fused with other members of Metastatic disease at presentation is the most significant adverse
the ETS gene family. In rare cases, FUS can substitute for EWS prognostic factor in Ewing sarcoma, as it is for other bone
resulting in fusion transcripts with no EWS rearrangement [FUS-ERG sarcomas.22,183,187 Lungs, bone, and bone marrow are the most common
fusion transcript resulting from the translocation t(16;21)(p11;q24) or sites of metastasis. In a retrospective analysis of 975 patients from the
FUS-FEV fusion transcript resulting from the translocation EICESS Study Group, 5-year RFS was 22% for patients with metastatic
t(2;16)(q35;p11)].174,175 Ewing sarcoma is also characterized by the disease at diagnosis compared with 55% for patients without
strong expression of cell surface glycoprotein MIC2 (CD99).176,177 The metastases at diagnosis.22 Among patients with metastases, there was
expression of MIC2 may be useful in the differential diagnosis of Ewing a trend for better survival for those with lung metastases compared to
sarcoma and primitive neuroectodermal tumor (PNET) from other small those with bone metastases or a combination of lung and bone
round-cell neoplasms, although it is not exclusively specific for these metastases.22 Metastases to uncommon sites (ie, brain, liver, spleen)
tumors.178 were associated with a worse prognosis in a retrospective study of 30
patients.188 Poor histologic/radiologic response to chemotherapy has
Typically, Ewing sarcoma occurs in adolescents and young adults. The also been identified as an adverse prognostic factor in patients with
most common primary sites are the pelvic bones, femur, and the bones localized non-metastatic disease,182,189,190 even when chemotherapy was
of the chest wall, although any bone may be affected.19 When arising in followed by R0 resection.191
a long bone, the diaphysis is the most frequently affected site. On
imaging, the bone appears mottled. Periosteal reaction is classic and it The results of the IESS study analyzing the clinicopathologic features of
is referred to as onion skin by radiologists. 303 cases of Ewing sarcoma showed that patients with primary tumors
in pelvic bones have lower survival rates compared with patients with
Patients with Ewing sarcoma, as with most patients with bone lesions in distal bones of the extremities.192 In a recent analysis of 53
sarcomas, seek attention because of localized pain or swelling. Unlike patients (24 adult and 29 pediatric) with Ewing sarcoma treated with
other bone sarcomas, constitutional symptoms such as fever, weight chemotherapy, Gupta et al identified pelvic disease and time to local
loss, and fatigue are occasionally noted at presentation. Abnormal therapy as significant prognostic factors associated with EFS in a
laboratory studies may include elevated serum LDH and leukocytosis. multivariate analysis.193 In another retrospective analysis of patients
with Ewing sarcoma from a large population-based cancer registry,
Prognostic Factors
Lee et al determined that adult age, Hispanic race, metastatic
The important indicators of favorable prognosis include a disease, large tumor size, and low socioeconomic status are poor
distal/peripheral site of primary disease, tumor volume <100 mL, prognostic factors for OS.194
normal LDH level at presentation, and the absence of metastatic
disease at the time of presentation.179-185 Ewing sarcoma in the spine
and sacrum is associated with significantly worse outcome and
prognosis than primary Ewing sarcoma in other sites.186

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Workup Treatment
If Ewing sarcoma is suspected as a diagnosis, the patient should Local Control Therapy
undergo complete staging prior to biopsy. This should include CT of the Surgery and RT are the local control treatment modalities used for
chest; MRI with or without CT of the primary site; PET/CT scan and/or patients with localized disease. There have been no randomized
bone scan; and bone marrow biopsy and/or screening MRI of the spine studies that have compared these two treatment modalities.
and pelvis. In a recent systematic review and meta-analysis, Treglia et
al have reported that the combination of PET/CT with conventional In patients with localized Ewing sarcoma treated in cooperative
imaging is a valuable tool for the staging and restaging of Ewing intergroup studies there was no significant effect of local control
sarcoma, with 96% sensitivity and 92% specificity.195 An ongoing modality (surgery, RT, or surgery plus RT) on OS or EFS rates.201,202 In
diagnostic study is comparing whole-body MRI and conventional the CESS 86 trial, although radical surgery and resection plus RT
imaging for detecting distant metastases in pediatric patients with resulted in better local control rates (100% and 95%, respectively) than
Ewing sarcoma, Hodgkins lymphoma, non-Hodgkins lymphoma, definitive RT (86%), there was no improvement in RFS or OS because
rhabdomyosarcoma, and neuroblastoma. of higher frequency of metastases after surgery.201 In the INT-0091
study, the incidences of local failure were similar for patients treated
Cytogenetic and/or molecular studies of the biopsy specimen should be with surgery or RT alone (25%), but surgery plus RT resulted in lower
performed to evaluate the t(11;22) translocation. Preliminary reports incidences of local failure (10.5%).202 The 5-year EFS rate was also not
suggest that EWS-FLI1 translocation is associated with a better significantly different between the groups (42%, 52%, and 47% for
prognosis than other variants.196-198 However, recent reports from the patients treated with surgery, RT, and surgery plus RT, respectively).
EURO-EWING 99 study and the Childrens Oncology Group study
suggest that with currently available effective therapies, patients with Data from other retrospective analyses suggest that surgery (with or
Ewing sarcoma have similar outcomes, regardless of fusion subtype in without postoperative RT) affords better local control than RT alone in
contrast to previous reports.199,200 In addition to EWS, FUS should be patients with localized disease.203,204 The combined analysis of 1058
considered as a fusion gene partner in the molecular diagnosis to patients treated in the CESS 81, CESS 86, and EICESS 92 trials
identify the rare cases of Ewing sarcoma with FUS-ERG or FUS-FEV showed that the rate of local failure was significantly lower after surgery
fusion transcripts.174,175 Bone marrow biopsy should be considered to (with or without postoperative RT) than after definitive RT (7.5% vs.
complete the workup. Since serum LDH has been shown to have 26.3%, respectively; P = .001), whereas the local control rate with
prognostic value as a tumor marker, the guidelines have included this preoperative RT was comparable to that of the surgery group (5.3%).203
test as part of initial evaluation. Fertility consultation should be The most recent retrospective analysis of sequential studies (INT-0091,
considered. INT-0154, or AEWS0031) performed by the Childrens Oncology Group
also demonstrated that definitive RT was associated with a higher risk
of local failure than surgery plus RT, but there was no effect on distant
failure.204 Definitive RT could be an effective treatment option for

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patients with tumors in anatomical locations not amenable to achieve in patients with localized non-metastatic disease.214 The 5-year RFS
surgery with wider resection margins.205,206 In a retrospective analysis of rate was 60% and 24% for VACD and VAC, respectively (P < .001).
patients with Ewing sarcoma of vertebrae treated in the CESS 81/86 The corresponding OS rate was 65% and 28% (P < .001).
and EICESS 92 studies, definitive RT resulted in a local control rate of
22.6%, which was comparable to those of other tumor sites treated with The addition of ifosfamide, alone or in combination with etoposide to
definitive RT; EFS and OS at 5 years were 47% and 58%, standard chemotherapy, has also been evaluated in patients with newly
respectively.205 Tumor size and RT dose have been shown to be diagnosed, non-metastatic Ewing sarcoma.215,218-222 In the Pediatric
predictive of local control rates in patients with non-metastatic Ewing Oncology Group-Childrens Cancer Group (POG-CCG) study
sarcoma treated with chemotherapy and definitive RT.207,208 Local (INT-0091), 398 patients with nonmetastatic Ewing sarcoma were
control therapy has also been associated with improved outcomes in randomized to receive chemotherapy with either VACD alone or
patients with primary metastatic disease.209-211 In the EURO-EWING 99 alternating with ifosfamide and etoposide (VACD-IE) for a total of 17
trial, the 3-year EFS was significantly lower in patients with primary cycles.215 The 5-year EFS rate was significantly higher in the VACD-IE
metastatic disease who did not receive any local control therapy group than the VACD alone group (69% and 54%, respectively; P
compared to those treated with local therapy for primary tumor.209 =.005). The 5-year OS rate was also significantly better among patients
Retrospective analysis of 198 patients from EURO-EWING 99 showed in the VACD-IE group (72% and 61%, respectively; P = .01). VACD-IE
no improvement of 5-year EFS associated with adjuvant RT in the also was associated with lower incidences of local failure (11%)
setting of completely resected disease of the chest wall.212 compared with VACD (30%) irrespective of the type of local control
therapy; 5-year cumulative incidences of local failure were 30% in the
Chemotherapy VACD arm compared with 11% in the VACD-IE arm.202
Multiagent chemotherapy regimens including ifosfamide and/or
cyclophosphamide, etoposide, doxorubicin and/or dactinomycin, and While dose escalation of alkylating agents in the VAC-IE regimen did
vincristine have been shown to be effective in patients with localized not improve the outcome for patients with localized disease,223
Ewing sarcoma in single- as well as multi-institution collaborative trials chemotherapy intensification through interval compression improved
in the United States and Europe. Neoadjuvant chemotherapy prior to outcome in patients with localized disease.224 In a randomized trial for
surgery downstages the tumor and increases the probability of patients younger than 50 years with localized Ewing sarcoma (n = 568),
achieving a complete resection with microscopically negative margins. Womer et al reported that VAC-IE given on an every-2-week schedule
Adjuvant chemotherapy following surgical resection improves RFS and was found to be more effective than VAC-IE given on an every-3-week
OS in a majority of patients.213-217 schedule, with no increase in toxicity; median 5-year EFS was 73% and
65%, respectively.224
IESS-I and IESS-II showed that RT plus adjuvant chemotherapy with
VACD (vincristine, dactinomycin, cyclophosphamide, and doxorubicin) The addition of ifosfamide and/or etoposide to standard chemotherapy
was superior to VAC (vincristine, dactinomycin, and cyclophosphamide) did not improve outcomes for patients with metastatic disease at

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diagnosis in all of the studies.215,218,220,225 In the INT 0091 study, which associated with a greater survival benefit in the subgroup of patients
included 120 patients with metastatic disease, there was no significant without metastases (P = .18) than in those with metastases (P = .84).226
difference in the EFS and OS rates between VACD-IE and VACD
regimens.215 The 5-year EFS rate was 22% for both regimens and the As a follow-up to the EICESS-92 study, the Euro-EWING99-R1 trial
5-year OS rate was 34% and 35% for the VACD-IE and VACD groups, evaluated cyclophosphamide as a replacement for ifosfamide as a part
respectively. In a study of 68 patients (44 patients with locoregional of consolidation therapy that also included vincristine and dactinomycin
disease and 24 patients with distant metastases), Kolb et al reported (VAC vs. VAI) after VIDE (vincristine, ifosfamide, doxorubicin, and
4-year EFS and OS rates of 82% and 89%, respectively, for patients etoposide) induction chemotherapy in 856 patients with standard-risk
with locoregional disease treated with intensive chemotherapy Ewing sarcoma. VAC was statistically not inferior to VAI, but was
(doxorubicin and vincristine with or without high-dose associated with a slight increase in events (-2.8% decrease in 3-year
cyclophosphamide) followed by ifosfamide and etoposide.220 In patients EFS). The proportion of patients experiencing severe hematologic
with distant metastases the corresponding survival rates were 12% and toxicity was slightly higher in the VAC arm, but renal tubular function
18%, respectively. Miser et al also reported similar findings in patients impairment was more significant for patients receiving VAI.227
with Ewing sarcoma or PNET of bone with metastases at diagnosis.225
High-dose Therapy Followed by Stem Cell Transplant
The EICESS-92 study investigated whether cyclophosphamide has a High-dose therapy followed by stem cell transplant (HDT/SCT) has
similar efficacy as ifosfamide in patients with standard-risk Ewing been evaluated in patients with localized as well as metastatic disease.
sarcoma (small localized tumors) and whether the addition of etoposide HDT/SCT has been associated with potential survival benefit in patients
to a regimen already containing ifosfamide improves survival in patients with non-metastatic disease.228,229 However, studies that have evaluated
with high-risk disease (large tumors or metastatic disease at HDT/SCT in patients with primary metastatic disease have shown
diagnosis).226 Patients with standard-risk disease were randomly conflicting results.230-235
assigned to VAIA (vincristine, dactinomycin, ifosfamide, and
The EURO-EWING 99 study is the first large randomized trial designed
doxorubicin; n = 76) followed by either VAIA or VACA (vincristine,
to evaluate the efficacy and safety of multiagent induction
dactinomycin, cyclophosphamide, and doxorubicin; n = 79).226 The
chemotherapy with six courses of VIDE, local treatment (surgery and/or
3-year EFS rates were 73% and 74%, respectively, for VACA and
RT), and HDT/SCT in 281 patients with Ewing sarcoma with primary
VAIA, suggesting that cyclophosphamide has the same efficacy as
disseminated disease.231 After a median follow-up of 3.8 years, the EFS
ifosfamide in this group of patients. Patients with high-risk disease were
and OS rates at 3 years for the entire study cohort were 27% and 34%,
randomly assigned to VAIA or VAIA plus etoposide (EVAIA). The
respectively.235 The EFS rates were 57% and 25%, respectively, for
3-year EFS rate was not significantly different between the two
patients with complete and partial response after HDT/SCT. Patients
treatment groups (52% and 47%, respectively, for EVAIA and VAIA).
age, tumor volume, and extent of metastatic spread were identified as
However, there was some evidence that the addition of etoposide was
relevant risk factors. The outcome of patients with and without

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HDT/SCT was not performed because of the bias introduced early in Adjuvant chemotherapy following wide excision or amputation is
the non-transplant group (82% of patients without HDT/SCT died after a recommended for all patients regardless of surgical margins. The panel
median time of 1 year). strongly recommends that the duration of chemotherapy following wide
excision should be between 28 and 49 weeks depending on the type of
regimen and the dosing schedule (category 1).213-215 The addition of
All patients with Ewing sarcoma should be treated with the following postoperative RT to chemotherapy is recommended for patients with
protocol: primary treatment followed by local control therapy and positive or very close surgical margins.203 Denbo et al recently reported
adjuvant treatment. Primary treatment consists of multiagent that in patients with smaller tumor size (<8 cm) and negative margins,
chemotherapy along with appropriate growth factor support for at least postoperative RT can be omitted without any decrement in OS.236 The
12 weeks (category 1). Longer duration could be considered for 15-year estimated OS for patients who received adjuvant RT was 80%
patients with metastatic disease based on response. VAC/IE compared to 100% for those who did not. The guidelines have included
(vincristine, doxorubicin, and cyclophosphamide alternating with adjuvant chemotherapy alone for patients treated with wide excision
ifosfamide and etoposide) is the preferred regimen for patients with and negative margins.
localized disease, whereas VAdriaC (vincristine, doxorubicin, and
cyclophosphamide) is the preferred regimen for patients with metastatic Progressive disease following primary treatment is best managed with
disease.215,220,225 See Bone Cancer Systemic Therapy Agents in the RT and/or surgery to primary site followed by chemotherapy or best
algorithm for a list of other chemotherapy regimens that are supportive care.
recommended for patients with localized and metastatic disease.
Disease should be restaged with imaging following primary treatment. Surveillance
Chest imaging should be performed with CT and primary site imaging Surveillance of patients with Ewing sarcoma should include a physical
should include MRI with or without CT and plain radiographs. PET/CT exam, CBC, and other laboratory studies. Surveillance of patients with
and/or bone scan can be used for restaging depending on the imaging Ewing sarcoma should include a physical exam, CBC and other
technique that was used in the initial workup. Patients with stable or laboratory studies, and cross sectional imaging (MRI with or without
improved disease after primary treatment should be treated with local CT) and plain radiographs of the primary site. Chest CT is
control therapy. recommended every 2 to 3 months. PET/CT or bone scan can be
considered. Surveillance intervals should be increased after 2 years.
Local control options include wide excision, definitive RT with Long-term surveillance should be performed annually after 5 years
chemotherapy, or amputation in selected cases.203,205,207,209 The choice (category 2B).237
of local control therapy should be individualized and is dependent on
tumor location, size, response to chemotherapy, patients age, Relapsed or Refractory Disease
anticipated morbidity, and patient preference.202 About 30% to 40% of patients with Ewing sarcoma experience
recurrence (local and/or distant) and have a very poor prognosis.

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Patients with a longer time to first recurrence have a better chance of Non-ifosfamide-based chemotherapy regimens have also demonstrated
survival following recurrence. Late relapse (2 years or more from the activity in patients with relapsed or refractory bone sarcomas.
time of original diagnosis), lung-only metastases, local recurrence that Docetaxel in combination with gemcitabine was found to be well
can be treated with radical surgery, and intensive chemotherapy are the tolerated, resulting in an overall objective response rate of 29% in
most favorable prognostic factors, whereas early relapse (less than 2 children and young adults with refractory bone sarcomas; median
years from the time of original diagnosis) with metastases in lungs duration of response was 4.8 months.248 Topoisomerase I inhibitors
and/or other sites, recurrence at local and distant sites, elevated LDH at (topotecan and irinotecan) in combination with cyclophosphamide and
initial diagnosis, and initial recurrence are considered adverse temozolomide have also been associated with favorable response rates
prognostic factors.238-241 In a recent retrospective analysis, site of first in patients with relapsed or refractory bone sarcomas.249-255 In a series
relapse and time to first relapse were significant prognostic factors for of 54 patients with relapsed or refractory Ewing sarcoma,
adult patients with localized Ewing sarcoma.242 The probability of 5-year cyclophosphamide and topotecan induced responses in 44% of
post-relapse survival was 50% and 13%, respectively, for patients with patients (35% of patients had complete response and 9% had partial
local and distant relapse. The probability of 5-year post-relapse survival response).250 After a median follow-up of 23 months, 26% of patients
was also significantly higher for patients with late relapse than for those were in continuous remission. In a retrospective analysis of patients
with early relapse.22,242,243 with recurrent or progressive Ewing sarcoma, irinotecan and
temozolomide resulted in an overall objective response rate of 63%.
Ifosfamide in combination with etoposide with or without carboplatin has The median time to progression (TTP) for all the evaluable patients (n =
been evaluated in clinical trials for the treatment of patients with 20) was 8.3 months (16.2 months for the subset of patients with
relapsed or refractory sarcoma.244,245 In a phase II study, the recurrent disease).253 Patients who were in a 2-year first remission and
combination of ifosfamide with mesna and etoposide was highly active those with primary localized disease had better median TTP compared
with acceptable toxicity in the treatment of recurrent sarcomas in to those who relapsed within 2 years from diagnosis and patients with
children and young adults.244 In phase I/II studies conducted by the metastatic disease at diagnosis.
Childrens Oncology Group, the overall response rate in patients with
recurrent or refractory sarcoma was 51%; OS at 1 and 2 years was Combination therapy with vincristine, irinotecan, and temozolomide also
49% and 28%, respectively. OS appeared significantly improved in appears to be active and well-tolerated in patients with relapsed or
patients whose disease had complete or partial response.245 A recent refractory Ewing sarcoma, with an overall response rate of 68.1%.256 A
review of 239 patients with Ewing sarcoma suggested the potential risk review of 107 patients with relapsed or refractory Ewing sarcoma
reduction benefit of high-dose versus conventional chemotherapy for examined the combination of etoposide with a platinum agent (ie,
treating first relapse.246 High-dose ifosfamide with or without etoposide cisplatin or carboplatin), suggesting that further study of
is included as a second-line therapy for relapsed, refractory, or etoposide/carboplatin may be warranted.257 HDT/SCT has been
metastatic disease.244,247 associated with improved long-term survival in patients with relapsed or

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progressive Ewing sarcoma in small, single-institution studies.258-260 The presence of metastatic disease. Bone scan can be considered for
role of this approach is yet to be determined in prospective randomized unusual cases. Biopsy is essential to confirm the diagnosis. Brown
studies. tumor of hyperparathyroidism should be considered as a differential
diagnosis, though routine evolution of serum calcium, phosphate, and
parathyroid hormone levels can help exclude this diagnosis.267
Treatment options for patients with relapsed or refractory disease
include participation in a clinical trial and chemotherapy with or without Treatment
RT. If a relapse is delayed, as sometimes occurs with this sarcoma, Surgery
re-treatment with a previously effective regimen may be useful. See Wide excision and intralesional curettage are the two surgical treatment
Bone Cancer Systemic Therapy Agents in the algorithm for a list of options for patients with resectable tumors.268-274 Wide excision is
other chemotherapy regimens recommended for patients with relapsed associated with a lower risk of local recurrence than intralesional
or refractory disease. curettage, with the local recurrence rates ranging from 0% to 12% for
wide excision and 12% to 65% for intralesional curettage. In some
All patients with recurrent and metastatic disease should be considered
studies, the extent of intralesional excision and the tumor stage have
for clinical trials investigating new treatment approaches.
been identified as prognostic indicators for risk of recurrence.275-277
Giant Cell Tumor of Bone Blackley et al reported a local recurrence rate of 12% in 59 patients
who were treated with curettage with high-speed burr and bone
GCTB is a rare benign primary tumor of the bone accounting for about
grafting, which was similar to that observed with the use of adjuvants;
3% to 5% of all primary bone tumors, with a strong tendency for local
the majority of the patients had grade II or III tumors.276 In another
recurrence and that may metastasize to the lungs.261,262 GCTB usually
retrospective analysis of 137 patients, Prosser et al reported local
occurs between 20 and 40 years of age. Distal femur and proximal tibia
recurrences in 19% of patients following curettage as a primary
are the most common primary sites. Malignant transformation to
treatment; local recurrence rate was only 7% for patients with grade I
high-grade osteosarcoma has been observed in rare cases and is
and II tumors confined to the bone compared with 29% for those with
associated with a poor prognosis.263,264
grade III tumors with extraosseous extension.277
Workup
Surgical adjuvants have been used in conjunction with intralesional
Initial workup should include history and physical examination with curettage to improve local control rates. However, the findings from
imaging (x-ray, CT with or without MRI) of the primary site as clinically studies that have evaluated intralesional curettage, with and without
indicated, in addition to chest imaging. CT is useful to define the extent adjuvant in the same cohort of patients with primary or recurrent GCTB,
of cortical destruction, whereas MRI is the preferred imaging modality are inconsistent, with some reporting decreased local recurrence rates
to assess the extension of tumors into the adjacent soft tissue and with the use of adjuvants.272,278-281 Others, however, have reported no
neurovascular structures.265,266 Chest imaging is essential to identify the

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significant difference in local recurrence rates with and without approved by the FDA for the treatment of adults and skeletally mature
adjuvants.124,282,283 adolescents with GCTB that is unresectable or where surgical resection
is likely to result in severe morbidity.
Wide excision is also associated with poor functional outcome and
greater surgical complications.284-288 Therefore, intralesional curettage is Several phase II trials have examined the efficacy of denosumab for
considered the treatment of choice in a majority of patients with stage I treating primary and recurrent GCTB. In an open-label, phase II study
or II tumors. Wide excision is usually reserved for more aggressive (n = 37), denosumab induced tumor response (defined as the
stage III tumors with extraosseous extension or otherwise unresectable elimination of at least 90% of giant cells or no radiologic progression of
tumors.277,289-292 the target lesion for up to 25 weeks) in 86% (30 of 35 evaluable
patients) of patients with unresectable or recurrent GCTB.307 Results
Radiation Therapy were recently reported from an open-label, parallel-group, phase II
RT has been used either as a primary treatment or in combination with study of patients with GCTB who were divided into 3 cohorts: those with
surgery to improve local control and DFS for patients with marginally unresectable GCTB (cohort 1), those with resectable GCTB associated
resected, unresectable, progressive, or recurrent disease.293-304 In a with severe surgical morbidity (cohort 2), and those transferred from a
recent retrospective analysis of 58 patients with GCTB (45 patients with previous study of denosumab for GCTB (cohort 3).309,311 After a median
primary tumor and 13 patients with recurrent tumor) treated with RT, follow-up of 13 months, 96% of evaluable patients (163 of 169) in
the 5-year local control and OS rates were 85% and 94%, cohort 1 had no disease progression.309 Clinically significant reductions
respectively.303 Median follow-up was 8 years. In this analysis, patient in pain were reported by over half of the study patients within 2
age was the only prognostic factor with the local control rates (96% for months.312 Final analysis of outcomes from cohort 2 (n = 222) showed
younger patients vs. 73% for the older group) as well as OS (100% vs. that denosumab enabled 48% of patients to delay/avoid surgery and
87%) and DFS rates (96% vs. 65%). Other studies have identified 38% to undergo less morbid resections. Treatment did not appear to
tumor size >4 cm, recurrent tumors, and RT doses of 40 Gy or less as worsen local control or increase recurrence rates compared with
negative prognostic factors for local control.299-301,304 historical data.311
Specialized techniques such as 3-D conformal RT and IMRT have also Recent phase II trial data have also suggested that sequential FDG-
been associated with good local control rates in patients with GCTB in PET imaging appears to be a sensitive tool for early detection of tumor
locations that are not amenable to complete surgical resection.305,306 response to denosumab treatment.313
Systemic Therapy
Denosumab (a fully humanized monoclonal antibody against the RANK
ligand) has demonstrated significant activity in patients with
unresectable or recurrent GCTB.307-310 In June 2013, denosumab was

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NCCN Recommendations localized disease.261,262,322,323 Intralesional excision is recommended for

resectable metastatic sites. Denosumab, IFN, observation, and RT are
Localized Disease
included as options for patients with unresectable metastases.
Intralesional excision with or without an effective adjuvant is an
adequate primary treatment for resectable tumors.124,282,283 Surveillance
Serial arterial embolizations have been shown to be effective in the Surveillance should include a physical exam, imaging (x-ray, MRI CT)
management of patients with giant cell tumors of the extremities, of the surgical site as clinically indicated, and chest imaging every 6
especially for tumors with large cortical defects or joint involvement and months for 2 years then annually thereafter.
for those with large giant cell tumors of the sacrum.314-317 A few case
Recurrent disease (local or metastatic) should be managed as per
reports have reported the efficacy of IFN and pegylated IFN in the
primary treatment for localized disease or metastatic disease at
management of GCTB.318-321
presentation.
For patients with lesions that are resectable with unacceptable
Osteosarcoma
morbidity or unresectable axial lesions, the guidelines have included
serial embolizations, denosumab, or IFN as primary treatment options. Osteosarcoma is the most common primary malignant bone tumor in
RT has been associated with increased risk of malignant transformation children and young adults. The median age for all patients with
and should be used in patients with tumors that are not amenable to osteosarcoma is 20 years. In adults older than 65 years, osteosarcoma
embolization, denosumab, or IFNs. Imaging should be used to assess develops as a secondary malignancy related to Pagets disease of the
treatment response and should include plain radiographs as well as CT bone.15 Osteosarcoma is broadly classified into three histologic
with or without MRI. subtypes (intramedullary, surface, and extraskeletal).324
Following primary treatment, patients with stable/improved disease can High-grade intramedullary osteosarcoma is the classic or conventional
be observed. For patients with stable/improved disease with incomplete form comprising nearly 80% of osteosarcoma.324 It is a spindle cell
healing following primary treatment, intralesional excision is tumor that produces osteoid or immature bone. The most frequent sites
recommended if the lesion has become resectable. Patients with are the metaphyseal areas of the distal femur or proximal tibia, which
unresectable disease should be retreated with serial embolization, are the sites of maximum growth. Low-grade intramedullary
and/or denosumab, and/or IFN. The guidelines recommend osteosarcoma comprises less than 2% of all osteosarcomas and the
continuation of treatment until disease progression. most common sites are similar to that of conventional osteosarcoma.325
Metastatic Disease Parosteal and periosteal osteosarcomas are juxtacortical or surface

variants. Parosteal osteosarcomas are low-grade lesions accounting for
For patients presenting with resectable metastases, the guidelines
up to 5% of all osteosarcomas.325 The most common site is the
recommend that primary tumor be managed as described above for

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posterior distal femur. This variant tends to metastasize later than the with increased chemotherapy-induced tumor necrosis and greater OS,
conventional form. Transformation of low-grade parosteal and children had better outcomes than adolescents and adults.339 In a
osteosarcoma into high-grade sarcoma has been documented in 24% recent report of the combined analysis of 3 European Osteosarcoma
to 43% of cases.326,327 Periosteal osteosarcomas are Intergroup randomized controlled trials, Whelan et al reported that good
intermediate-grade lesions most often involving the femur followed by histologic response to preoperative chemotherapy, distal location (other
the tibia.325 High-grade surface osteosarcomas are very rare accounting than proximal humerus/femur), and female gender were associated
for 10% of all juxtacortical osteosarcomas.328,329 with improved survival.335 However, high body mass index (BMI) in
patients with osteosarcoma was associated with lower OS compared
Pain and swelling are the most frequent early symptoms. Pain is often with patients with normal BMI.340
intermittent in the beginning and a thorough workup sometimes is
delayed because symptoms may be confused with growing pains. In patients with proven primary metastatic osteosarcoma, the number of
Osteosarcoma spreads hematogenously, with the lung being the most metastases at diagnosis and the completeness of surgical resection of
common metastatic site. all clinically detected tumor sites are of independent prognostic value.23
Patients with one or a few resectable pulmonary metastases have a
For treating extraskeletal osteosarcomas, please see the NCCN survival rate that approaches that of patients with no metastatic
Guidelines for Soft Tissue Sarcoma. disease.341,342
Prognostic Factors Elevated serum ALP and LDH levels have also been identified as
Tumor site and size, patient age, presence and location of metastases, prognostic indicators in patients with osteosarcoma.331,333,334 In a cohort
histologic response to chemotherapy, and type of surgery and surgical of 1421 patients with osteosarcoma of the extremity, Bacci et al
margins are significant prognostic factors for patients with reported significantly higher serum LDH levels in patients with
osteosarcoma of the extremities and trunk.330-338 In an analysis of 1702 metastatic disease at presentation than in patients with localized
patients with osteosarcoma of trunk or extremities treated in the COSS disease (36.6% vs. 18.8%; P < .0001).333 The 5-year DFS correlated
group protocols, patient age at diagnosis, tumor site, and primary with serum LDH levels (39.5% for patients with high LDH levels and
metastases were identified as predictors of survival.332 In patients with 60% for those with normal values). In another retrospective analysis of
extremity osteosarcomas, in addition to these variables, size and 789 patients with osteosarcoma of the extremity, Bacci et al reported
location within the limb at the time of diagnosis also had significant that the serum ALP level was a significant prognostic factor of EFS in
influence on outcome.332 All factors except age were significant in patients with osteosarcoma of extremity; the 5-year EFS rate was 24%
multivariate testing, with surgical remission and histologic response to for patients with a serum ALP value of more than 4 times higher than
chemotherapy emerging as the key prognostic factors. In a recent the normal value and 46% for patients with high values below this limit
meta-analysis of data from prospective neoadjuvant chemotherapy (P < 0.001).334 However, in multivariate analysis, these markers did not
trials in 4838 patients with osteosarcoma, female sex was associated

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retain their prognostic significance when compared to tumor volume, osteosarcomas with good histologic response to neoadjuvant
age, and histologic response to chemotherapy.331,333 chemotherapy, limb-sparing surgery is considered the preferred
surgical modality if wide surgical margins could be achieved.344,348
Workup Amputation is generally reserved for patients with tumors in unfavorable
Osteosarcomas present both a local problem and a concern for distant anatomical locations not amenable to limb-sparing surgery with
metastasis. Initial workup should include imaging of the primary site adequate surgical margins.343,348
(MRI with or without CT), chest imaging including chest CT, and
PET/CT and/or bone scan. More detailed imaging (CT or MRI) of Chemotherapy
abnormalities identified on primary imaging is required for suspected The addition of adjuvant and neoadjuvant chemotherapy regimens to
metastatic disease. surgery has improved outcomes in patients with localized
osteosarcoma. Early trials used chemotherapy regimens including at
Plain radiographs of osteosarcomas show cortical destruction and least three or more of the following drugs: doxorubicin, cisplatin,
irregular reactive bone formation. Bone scan, while uniformly abnormal bleomycin, cyclophosphamide or ifosfamide, dactinomycin, and
at the lesion, may be useful to identify additional synchronous lesions. high-dose methotrexate.349-354 Subsequent clinical trials have
MRI provides excellent soft-tissue contrast and may be essential for demonstrated that short, intensive chemotherapy regimens including
operative planning. MRI is the best imaging modality to define the cisplatin and doxorubicin with or without high-dose methotrexate and
extent of the lesion within the bone as well as within the soft tissues, to ifosfamide produce excellent long-term results, similar to those
detect skip metastases and to evaluate anatomic relationships with achieved with multiagent chemotherapy.355-362
the surrounding structures. In addition, ALP and LDH are frequently
elevated in patients with osteosarcoma. Serum LDH was significantly In a randomized trial conducted by the European Osteosarcoma Group,
higher in patients with metastatic disease at presentation than in the combination of doxorubicin and cisplatin was better tolerated
patients with localized disease.333 compared to a multi-drug regimen with no difference in survival
between the groups in patients with operable, non-metastatic
Treatment osteosarcoma.356 The 3-year and 5-year OS rates were 65% and 55%,
Surgery respectively, in both groups. The 5-year PFS rate was 44% in both
Surgery (limb-sparing surgery or amputation) remains an essential part groups. In the INT-0133 study, which compared the 3-drug regimen
of management of patients with osteosarcoma.343 Studies that have (cisplatin, doxorubicin, and methotrexate) with the 4-drug regimen
compared limb-sparing surgery and amputation in patients with (cisplatin, doxorubicin, methotrexate, and ifosfamide) for the treatment
high-grade, non-metastatic osteosarcoma have not shown any of patients with non-metastatic resectable osteosarcoma, there was no
significant difference in survival and local recurrence rates between difference in the 6-year EFS (63% and 64%, respectively) and OS (74%
these procedures.344-346 However, limb-sparing surgery is associated and 70%, respectively) between the two groups.362
with better functional outcomes.347 In patients with high-grade

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Chemotherapy regimens without doxorubicin or cisplatin have also associated with a statistically significant improvement in 6-year OS
been evaluated in patients with localized osteosarcoma with the aim of (70%78%) and a trend toward better EFS in patients with
minimizing long-term cardiotoxicity and ototoxicity.363,364 In a phase II non-metastatic resectable osteosarcoma.362 However, the improvement
study, the combination of cisplatin, ifosfamide, and epirubicin was was not statistically different in patients with metastatic disease.368
active and reasonably well tolerated in patients with nonmetastatic MTP-PE is not approved by the FDA for the treatment of patients with
extremity osteosarcoma.363 With a median follow-up of 64 months, the osteosarcoma.
5-year DFS and OS rates were 41.9% and 48.2%, respectively. In
another randomized multicenter trial (SFOP-OS94), the combination of Localized Disease
ifosfamide and etoposide resulted in a higher histologic response rate The guidelines recommend wide excision as the primary treatment for
than the regimen containing high-dose methotrexate and doxorubicin patients with low-grade (intramedullary and surface) osteosarcomas
(56% and 39%, respectively). However, the 5-year OS was similar in and periosteal lesions. Chemotherapy prior to wide excision could be
both arms and there was no significant difference in 5-year EFS considered for patients with periosteal lesions. Although
rates.364 chemotherapy (neoadjuvant or adjuvant) has been used in the
treatment of patients with periosteal osteosarcoma, there are no data
Good histopathologic response (greater than 90% necrosis) to to support that the addition of chemotherapy to wide excision
neoadjuvant chemotherapy has been shown to be predictive of survival improves outcome in patients with periosteal osteosarcoma.369,370 In a
regardless of the type of chemotherapy administered after review of 119 patients with periosteal sarcoma published by the
surgery.237,365,366 In an analysis of 881 patients with non-metastatic European Musculo-Skeletal Oncology Society, the use of neoadjuvant
osteosarcoma of the extremities treated with neoadjuvant chemotherapy was not a prognostic factor, although it was used in the
chemotherapy and surgery at the Rizzoli Institute, Bacci et al showed majority of the patients.370 More recently, Cesari and colleagues also
that the 5-year DFS and OS correlated significantly with histologic reported similar findings; the 10-year OS rate was 86% and 83%,
response to chemotherapy.367 The 5-year DFS and OS in good and respectively, for patients who received adjuvant chemotherapy with
poor responders were 67.9% vs. 51.3% (P < .0001) and 78.4% vs. surgery and for those who underwent surgery alone (P = .73).369 Long-
63.7% (P < .0001), respectively. A report from the Children's Oncology term results (>25 years of follow-up) from patients with high-grade,
Group also confirmed these findings; the 8-year postoperative EFS and localized osteosarcoma reveal significant benefits of adjuvant
OS rates were 81% and 87%, respectively, in good responders.365 The chemotherapy on DFS and OS.366
corresponding survival rates were 46% and 52%, respectively, in poor
responders. Following wide excision (of resectable lesions), the guidelines have
included postoperative chemotherapy with a category 2B
The addition of muramyl tripeptide phosphatidylethanolamine (MTP-PE) recommendation for patients with low-grade (intramedullary and
to chemotherapy has also been evaluated in patients with
osteosarcoma.362,368 The addition of MTP-PE to chemotherapy was

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surface) or periosteal sarcomas with pathologic findings of high-grade preoperative chemotherapy. The EURAMOS-1 trial included cohorts
disease. that received maintenance therapy with MAP
(methotrexate/cisplatin/doxorubicin); MAP with pegylated interferon
Preoperative chemotherapy prior to wide excision is preferred for (IFN)--2b therapy; or MAP with ifosfamide and etoposide (MAPIE).
those with high-grade osteosarcoma (category 1).341,355-357,360-364,371 The addition of maintenance pegylated IFN--2b therapy to MAP in the
Repeat imaging using pretreatment imaging modalities should be used adjuvant setting did not improve outcomes for good responders to
to reassess the tumor for resectability. Selected elderly patients may preoperative chemotherapy.380 However, the authors note that a
benefit from immediate surgery. significant portion of patients in the IFN arm did not receive the
intended dose of IFN--2b due to failure to initiate therapy or premature
Following wide excision, patients whose disease has a good histologic
termination of therapy. Additionally, adding ifosfamide and etoposide to
response (amount of viable tumor is less than 10% of the tumor area)
MAP (ie, MAPIE) failed to improve outcomes for poor responders to
should continue to receive several more cycles of the same
preoperative chemotherapy.376,381
chemotherapy. Patients whose disease has a poor response (viable
tumor is 10% of the tumor area) could be considered for Chemotherapy should include appropriate growth factor support. See
chemotherapy with a different regimen (category 2B). However, the NCCN Guidelines for Myeloid Growth Factors in Cancer Treatment
attempts to improve the outcome of poor responders by modifying the for growth factor support. See Bone Cancer Systemic Therapy Agents
adjuvant chemotherapy remain unsuccessful.372-376,382 Upon review of in the algorithm for a list of specific chemotherapy regimens.
the evidence, this recommendation was changed from category 2A to
category 2B. Surgical re-resection with or without RT can be Metastatic Disease at Presentation
considered for positive surgical margins. In a study of 119 patients with Approximately 10% to 20% of patients present with metastatic disease
osteosarcoma of the head and neck, combined modality treatment with at diagnosis.23,382 The number of metastases at diagnosis and complete
surgery and RT (vs. surgery alone) improved local control and OS for surgical resection of all clinically detected tumor sites are of
patients with positive or uncertain surgical margins.377 Combined independent prognostic value in patients with primary metastatic
photon/proton or proton beam RT has been shown to be effective for disease at presentation.23 Unilateral metastases and lower number of
local control in some patients with unresectable or incompletely lung nodules were associated with improved outcomes with
resected osteosarcoma.378,379 chemotherapy in patients with synchronous lung metastases.341,342 The
2-year DFS rate was significantly higher for patients with only one or
An ongoing randomized phase III trial of the European and American
two metastatic lesions than for patients with 3 or more lesions (78%
Osteosarcoma Study (EURAMOS) Group is evaluating treatment
and 28%, respectively).341
strategies for resectable osteosarcoma based on histologic response to
preoperative chemotherapy. RT or adjuvant chemotherapy is Although chemotherapy is associated with improved outcomes in
recommended if the sarcoma remains unresectable following patients with non-metastatic, high-grade, localized osteosarcoma, the

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results were significantly poorer in patients with metastatic disease at years 4 and 5, and annually thereafter. Surveillance should include a
presentation.382-384 In a study of 57 patients with metastatic disease at complete physical, chest imaging, and imaging of the primary site as
presentation treated with cisplatin, doxorubicin, and high dose of performed during initial disease workup. PET/CT and/or bone scan
methotrexate and ifosfamide, the 2-year EFS and OS rates were 21% (category 2B) may also be considered. Functional reassessment should
and 55%, respectively, compared to 75% and 94% in patients with be performed at every visit.
non-metastatic disease at presentation, treated with the same
chemotherapy protocol.384 High-dose ifosfamide plus etoposide was Relapsed or Refractory Disease
examined in a phase II/III trial of 43 patients with newly diagnosed About 30% of patients with localized disease and 80% of the patients
metastatic osteosarcoma, revealing an overall response rate of 59% presenting with metastatic disease will relapse. The presence of solitary
8%, but considerable toxicity.385 metastases, time to first relapse, and complete resectability of the
disease at first recurrence have been reported to be the most important
Among patients with primary metastases treated in cooperative prognostic indicators for improved survival, whereas patients not
osteosarcoma trials, long-term survival rates were higher for patients amenable to surgery and those with a second or a third recurrence
whose metastases were excised following chemotherapy and surgery have a poor prognosis.388-393 In patients with primary non-metastatic
of the primary tumor compared to those patients whose metastases osteosarcoma, a longer relapse-free interval to pulmonary metastases
could not be removed (48% and 5%, respectively).386 The combination was significantly associated with better survival.391 The prognostic
of aggressive chemotherapy with simultaneous resection of primary significance of surgical clearance among patients with second and
and metastatic lesions has also resulted in improved outcomes in subsequent recurrences was also confirmed in a recent report of
patients with osteosarcoma of the extremity with lung metastases at survival estimates derived from large cohorts of unselected patients
presentation.387 treated at the COSS group trials.394
For patients with resectable metastases (pulmonary, visceral, or The combination of etoposide with cyclophosphamide or ifosfamide has
skeletal) at presentation, the guidelines recommend preoperative been evaluated in clinical trials.244,395,396 In a phase II trial of the French
chemotherapy followed by wide excision of the primary tumor. Society of Pediatric Oncology, high-dose ifosfamide and etoposide
Chemotherapy and metastasectomy are included as options for the resulted in a response rate of 48% in patients with relapsed or
management of metastatic disease. Unresectable metastatic disease refractory osteosarcoma.396 In another phase II trial, cyclophosphamide
should be managed with chemotherapy and/or RT followed by and etoposide resulted in a 19% response rate and 35% rate of stable
reassessment of the primary site for local control. disease in patients with relapsed high-risk osteosarcoma.395 PFS at 4
months was 42%.
Surveillance
Once treatment is completed, surveillance should occur every 3 months Single-agent gemcitabine and combination regimens such as docetaxel
for 2 years, then every 4 months for year 3, then every 6 months for and gemcitabine, cyclophosphamide and topotecan, ifosfamide,

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carboplatin, and etoposide have also been effective in the treatment of (defined as no progression at 6 months) was 29%. Partial response and
patients with relapsed or refractory bone sarcomas.245,248,252,397,398 stable disease were seen in 8% and 34% of patients, respectively, and
were durable for 6 months or more in 17% of patients.
Samarium-153 ethylenediamine tetramethylene phosphonate (Sm 153-
EDTMP) is a beta particleemitting bone-seeking radiopharmaceutical, To extend the duration of activity, a recent study examined sorafenib
and has been evaluated in patients with locally recurrent or metastatic combined with everolimus for patients with unresectable or relapsed
osteosarcoma or skeletal metastases.399,400 Andersen et al have high-grade osteosarcoma (n = 38).405 Data suggested that this regimen
reported that Sm 153-EDTMP with peripheral blood progenitor cell is active in the second-line setting, but toxicity required dose reductions
support had low non-hematologic toxicity and provided pain palliation and/or treatment interruptions in 66% of patients.
for patients with osteosarcoma local recurrences or osteoblastic bone
metastases.399 Results of a dose finding study also demonstrated that The safety and efficacy of HDT/SCT in patients with locally advanced,
Sm 153-EDTMP can be effective in the treatment of patients with metastatic, or relapsed osteosarcoma has also been evaluated.406,407 In
high-risk osteosarcoma.400 the Italian Sarcoma Group study, treatment with carboplatin and
etoposide was followed by stem cell rescue, combined with
Radium-223 dichloride (Ra 223) is a bone-seeking, alpha particle surgery-induced complete response in chemosensitive disease.407
emitting radiopharmaceutical that is under early-stage investigation for Transplant-related mortality was 3.1%. The 3-year OS and DFS rates
treating metastatic or recurrent osteosarcoma.401,402 This agent is were 20% and 12%, respectively. The efficacy of this approach in
approved in the United States for treating bone metastases associated patients with high-risk disease is yet to be determined in prospective
with castration-resistant prostate cancer. Preliminary studies suggest randomized studies.
that this agent is active in osteosarcoma and may have less marrow
toxicity and greater efficacy than beta particleemitting The optimal treatment strategy for patients with relapsed or refractory
radiopharmaceuticals such as Sm 153-EDTMP.402,403 disease has yet to be defined. If relapse occurs, the patient should
receive second-line chemotherapy and/or surgical resection when
Targeted inhibition of a variety of molecular pathways such as mTOR, feasible, followed by imaging to assess treatment response. Based on
SRC family of kinases, and vascular endothelial growth factor receptors the results of the recent phase II trial, the guidelines have included
(VEGFRs) are being evaluated in clinical trials to improve outcomes in sorafenib as a systemic therapy option for patients with relapsed
patients with relapsed or refractory osteosarcoma. In a phase II trial of disease.404 See the Bone Cancer Systemic Therapy Agents in the
the Italian Sarcoma Group (n = 30), sorafenib (VEGFR inhibitor) guidelines for a list of other second-line chemotherapy regimens.
demonstrated activity in patients with relapsed and unresectable Surveillance is recommended for patients with disease that is
high-grade osteosarcoma after failure of standard multimodal responding to second-line therapy.
therapy.404 The PFS at 4 months (primary endpoint) was 46%. Median
PFS and OS were 4 months and 7 months, respectively. The CBR

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Patients with disease progression or relapse after second-line therapy aggressive, non-pelvic, low-grade chondrosarcomas. Proton and/or
could be managed with resection, palliative RT, or best supportive care. photon beam RT may be useful for patients with chondrosarcomas of
The guidelines have also included Ra 223 and Sm 153-EDTMP as the skull base and axial skeleton with tumors in unfavorable location not
options for this group of patients. Participation in a clinical trial should amenable to resection. Chemotherapy has no role in the management
be strongly encouraged. of patients with chondrosarcoma, apart from the mesenchymal and
dedifferentiated subtypes.
High-grade Undifferentiated Pleomorphic Sarcoma of
Bone Chordomas arise from the embryonic remnants of the notochord and
High-grade UPS of the bone most frequently arises in the appendicular are more common in older adults. For patients with resectable
skeleton and is associated with both a high rate of local recurrence and conventional or chondroid chordomas, wide excision with or without RT
local nodal and distal metastases.408 The addition of chemotherapy to is the primary treatment option for chordomas of the sacrum and mobile
surgery has been shown to improve clinical outcomes in patients with spine, whereas intralesional excision with or without RT is the treatment
nonmetastatic malignant fibrous histiocytoma (MFH).409-411 In the of choice for skull base tumors. Adjuvant RT can be considered for
European Osteosarcoma Intergroup study, adjuvant or neoadjuvant large extracompartmental tumors or for positive surgical margins
chemotherapy with doxorubicin and cisplatin resulted in good following resection. RT is the primary treatment option for patients with
pathologic response rates and survivals (quite comparable with those unresectable chordomas, irrespective of the location of the tumor.
for osteosarcoma) in patients with nonmetastatic MFH.411 Median Systemic therapy (alone or in combination with surgery or RT) is
survival time was 63 months, and the 5-year PFS and OS rates were recommended for patients with recurrent tumors. Dedifferentiated
56% and 59%, respectively. The guidelines recommend that patients chordomas are usually managed as described in the NCCN Guidelines
with high-grade UPS of bone should be managed with regimens listed for Soft Tissue Sarcoma.
for osteosarcoma.
Ewing sarcoma develops mainly in children and young adults.
Summary EWS-FLI1 fusion gene resulting from t(11;22) chromosomal
translocation is the cytogenetic abnormality in the majority of patients.
Primary bone cancers are extremely rare neoplasms. Osteosarcoma,
Multiagent chemotherapy is the primary treatment and patients with
chondrosarcoma, and Ewing sarcoma are the three most common
disease that responds to primary treatment are treated with local
forms of primary bone cancers. High-grade UPS, chordoma, and GCTB
control therapy (wide excision, definitive RT with chemotherapy, or
are very rare.
amputation in selected cases) followed by adjuvant chemotherapy.
Chondrosarcoma is usually found in middle-aged and older adults. Adjuvant chemotherapy following wide excision or amputation is
Wide excision is the preferred treatment for resectable low- and recommended for all patients regardless of surgical margins.
high-grade chondrosarcomas. Intralesional excision with or without Progressive disease is best managed with RT with or without surgery
surgical adjuvant is an alternative option for less radiographically followed by chemotherapy or best supportive care.

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GCTB is the most common benign bone tumor predominant in young

adults. Intralesional excision with or without an effective adjuvant is an
adequate primary treatment for resectable tumors. Serial embolizations,
denosumab, and IFN are included as primary treatment options for
patients with lesions that are resectable with acceptable morbidity or
unresectable axial lesions. The guidelines recommend continuation of
denosumab until disease progression in responding disease.
Osteosarcoma occurs mainly in children and young adults. Wide

excision is the primary treatment for patients with low-grade
osteosarcomas, whereas preoperative chemotherapy followed by
wide excision is the preferred option for patients with high-grade
osteosarcoma. Chemotherapy prior to wide excision can be
considered for patients with periosteal lesions. Following wide
excision, postoperative chemotherapy is recommended for patients
with low-grade or periosteal sarcomas with pathologic findings of
high-grade disease and those with high-grade sarcoma. RT followed
by adjuvant chemotherapy is recommended if the sarcoma remains
unresectable after preoperative chemotherapy. Patients with relapsed
or refractory disease should be treated with second-line therapy.
Progressive disease is managed with surgery, palliative RT, or best
supportive care. Preoperative chemotherapy followed by wide excision
of the primary and metastatic tumors is recommended for patients with
resectable metastases. Chemotherapy and metastasectomy are
included as options for the management of metastatic disease.
Consistent with the NCCN philosophy, the panel encourages patients to
participate in well-designed clinical trials to enable further advances.

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

NCCN Guidelines Version 2.2017 Panel Members NCCN Guidelines Index

*J. Sybil Biermann, MD/Chair Nicola Fabbri, MD R. Lor Randall, MD

Mark Agulnik, MD David Lucas, MD Robert L. Satcher, MD, PhD

Robert S. Benjamin, MD Joel Mayerson, MD Herbert Schwartz, MD

NCCN Guidelines Version 2.2017 Table of Contents NCCN Guidelines Index

NCCN Bone Cancer Panel Members Osteosarcoma:

NCCN Guidelines Version 2.2017 Updates NCCN Guidelines Index

Giant Cell Tumor of the Bone:

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 Updates NCCN Guidelines Index

Bone Cancer Systemic Therapy Agents:

Principles of Radiation Therapy:

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

Specialists Critical in Certain Cases

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

aSee Multidisciplinary Team (TEAM-1).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

WORKUPa,b HISTOLOGIC SUBTYPE

aSee Multidisciplinary Team (TEAM-1).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

PRESENTATION PRIMARY TREATMENT ADJUVANT TREATMENT

Wide resectionb Consider RTd,e

bSee Principles of Bone Cancer Management (BONE-A).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

SURVEILLANCE RECURRENCE TREATMENT

bSee Principles of Bone Cancer Management (BONE-A).

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

PRESENTATIONa,b,c WORKUP PRIMARY RESTAGE

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

LOCAL CONTROL ADJUVANT TREATMENT/ PROGRESSIVE

Progressive disease Consider RTl and/or Chemotherapyf

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

Localized disease See GCTB-2

History and physical examination

aBrown tumor of hyperparathyroidism should be considered as a differential diagnosis.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

Resectable Excisionc See

For primary tumor, treat as above

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

Consider chest Consider denosumab prior

Physical exam Resectable

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

WORKUPa,b PRIMARY TREATMENT ADJUVANT TREATMENT

Low-grade osteosarcoma:c Wide High Chemotherapyd

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

NEOADJUVANT ADJUVANT TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2017 NCCN Guidelines Index

PRESENTATION PRIMARY TREATMENT